NCBI Conserved Domain Search

C2 domain present in Intersectin; A single instance of the C2 domain is located C terminally in the intersectin protein. Intersectin functions as a scaffolding protein, providing a link between the actin cytoskeleton and the components of endocytosis and plays a role in signal transduction. In addition to C2, intersectin contains several additional domains including: Eps15 homology domains, SH3 domains, a RhoGEF domain, and a PH domain. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. The members here have topology I.

Pssm-ID: 176021 [Multi-domain] Cd Length: 136 Bit Score: 243.83 E-value: 1.35e-74

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1497 EKAYQARSQKNSGIGRLLVTVLEATELKPCKPNGKSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCL 1576
Cdd:cd08375     1 EKAYLARSQRASGIGRLMVVIVEGRDLKPCNSNGKSDPYCEVSMGSQEHKTKVVSDTLNPKWNSSMQFFVKDLEQDVLCI 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146 1577 TVFERDQFSPDDFLGRTEVPVATIKKD-QDGKGPLVRRLLLHEVPTGEVKVRLDLQ 1631
Cdd:cd08375    81 TVFDRDFFSPDDFLGRTEIRVADILKEtKESKGPITKRLLLHEVPTGEVVVKLDLQ 136

Pleckstrin homology domain;

Pssm-ID: 465218 Cd Length: 143 Bit Score: 243.84 E-value: 1.76e-74

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  1356 VLCDGVIEHLVFNSLTNCLGPRKLLHSGKLHKTKSSKELWALLFNDFLLLTYTSKQFSSS-PDKLFNPNSNTQYKMYKTP 1434
Cdd:pfam16652    1 VQCEGLSEQLVFNSLTNCLGPRKLLHSGKLYKVKSNKELVGFLFNDFLLLTQPVKPLSSAgTDKLFSSKSNIQYKMYKTP 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 688602146  1435 VFLNEVLVKMPSDPSSDDPVFHISHIDRVYTLKTDTINERTTWVQKIKAASDHFIETEKLKRE 1497
Cdd:pfam16652   81 IFLNEVMVKLPTDPSSSEPTFQLSHIDRVYTLKAESPNERTAWVKKIKEASELYIETEKKKRE 143

Intersectin Pleckstrin homology (PH) domain; ITSNs, an adaptor protein family, play a role in endo- and exocytosis, actin cytoskeleton rearrangement and signal transduction. There are two human ITSN genes: ITSN1 and ITSN2. They share significant sequence identity and a similar domain structure having both short and long isoforms produced by alternative splicing. The short isoform (ITSN-S) consists of two Eps15 homology domains (EH1 and EH2), a coiled-coil region (CCR) and five Src homology 3 domains (SH3A-E). The EH domains bind to Asn-Pro-Phe motifs and are implicated in endocytosis and vesicle transport. The SH3 domains bind to proline-rich sequences and are commonly found in proteins implicated in cell signalling pathways, cytoskeletal organization and membrane traffic. The long isoform (ITSN-L) contains three additional C-terminal domains, a Dbl homology domain (DH), a Pleckstrin homology domain (PH) and a C2 domain. The tandem DH-PH domains are present in all Dbl family of GEFs. ITSN acts specifically on Cdc42 through its DH domain with no portion of the PH domain making contact with Cdc42. This is in contrast to Dbs which requires the PH domain for full catalytic activity. The ITSN PH domain binds phosphoinositides. C2 domains are usually involved in Ca2+-dependent and Ca2+-independent phospholipid binding. There are more than 30 proteins that interact with ITSNs. ITSN-S is present in mammals, frogs, flies and nematodes, while ITSN-L is present only in vertebrates. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 270084 Cd Length: 132 Bit Score: 223.10 E-value: 1.96e-67

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1365 LVFNSLTNCLGPRKLLHSGKLHKTKSSKELWALLFNDFLLLTYTSKQFSSSP-DKLFNPNSNTQYKMYKTPVFLNEVLVK 1443
Cdd:cd13264     2 LIFNSVTNCLGPRKFLHSGKLYKAKSNKELYGFLFNDFLLLTQPIKPLGSSGnDFVFDNKANIQYKMYKTPIFLNEVLVK 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1444 MPSDPSSDDPVFHISHIDRVYTLKTDTINERTTWVQKIKAASDHFIETEK 1493
Cdd:cd13264    82 LPTDPSGDEPIFHISHIDRVYTLRAESINERTAWVQKIKAASELYIETEK 131

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains.

Pssm-ID: 238091 [Multi-domain] Cd Length: 181 Bit Score: 175.56 E-value: 4.06e-50

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1154 RQGYIHELIQTEESYLEDLELAVEVFYKPMAESG-RLTEAEISMIFVNWRELIMCSTKLLKALRVRKKTagERMPVQVVG 1232
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELlPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEE--WDKSGPRIG 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1233 DILSSELSHMQAYIRFCSCQLNAAALLQQKTDKSLDFKLFLKKIasNYRCKGMPLSSFLLKPMQRITRYPLLIKNILENT 1312
Cdd:cd00160    79 DVFLKLAPFFKIYSEYCSNHPDALELLKKLKKFNKFFQEFLEKA--ESECGRLKLESLLLKPVQRLTKYPLLLKELLKHT 156

                         170       180
                  ....*....|....*....|....*
gi 688602146 1313 PPAHADHSNLQAALEQAEELCSQVN 1337
Cdd:cd00160   157 PDGHEDREDLKKALEAIKEVASQVN 181

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

Pssm-ID: 459876 [Multi-domain] Cd Length: 176 Bit Score: 172.48 E-value: 4.32e-49

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  1158 IHELIQTEESYLEDLELAVEVFYKPMAESGRLTEAEISMIFVNWRELIMCSTKLLkaLRVRKKtagERMPVQVVGDILSS 1237
Cdd:pfam00621    2 IKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL--LEELLK---EWISIQRIGDIFLK 76

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  1238 ELSHMQAYIRFCSCQLNAAALLQQKTDKSLDFKLFLKKIASNYRCKGMPLSSFLLKPMQRITRYPLLIKNILENTPPAHA 1317
Cdd:pfam00621   77 FAPGFKVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPDHP 156

                          170       180
                   ....*....|....*....|
gi 688602146  1318 DHSNLQAALEQAEELCSQVN 1337
Cdd:pfam00621  157 DYEDLKKALEAIKEVAKQIN 176

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

Pssm-ID: 214619 [Multi-domain] Cd Length: 180 Bit Score: 171.71 E-value: 8.19e-49

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   1158 IHELIQTEESYLEDLELAVEVFYKPMAESGR-LTEAEISMIFVNWRELIMCSTKLLKALRVRKKTAgeRMPVQVVGDILS 1236
Cdd:smart00325    2 LKELLQTERNYVRDLKLLVEVFLKPLKKELKlLSPNELETLFGNIEEIYEFHRDFLDELEERIEEW--DDSVERIGDVFL 79

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   1237 SELSHMQAYIRFCSCQLNAAALLQQKTDKSlDFKLFLKKIASNYRCKGMPLSSFLLKPMQRITRYPLLIKNILENTPPAH 1316
Cdd:smart00325   80 KLEEFFKIYSEYCSNHPDALELLKKLKKNP-RFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELLKHTPEDH 158

                           170       180
                    ....*....|....*....|..
gi 688602146   1317 ADHSNLQAALEQAEELCSQVNE 1338
Cdd:smart00325  159 EDREDLKKALKAIKELANQVNE 180

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

Pssm-ID: 197477 [Multi-domain] Cd Length: 96 Bit Score: 127.39 E-value: 2.29e-34

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146      7 IWAITPEERGKHDKQFDSLAPT-LGYLSGDQARKFFLQSGLPTSVLADIWALADIGKDGKMDRLEFSIAMKLIKLQLQGQ 85
Cdd:smart00027    1 PWAISPEDKAKYEQIFRSLDKNqDGTVTGAQAKPILLKSGLPQTLLAKIWNLADIDNDGELDKDEFALAMHLIYRKLNGY 80


                    ....*..
gi 688602146     86 PLPSSLP 92
Cdd:smart00027   81 PIPASLP 87

Fourth Src homology 3 domain (or SH3D) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fourth SH3 domain (or SH3D) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212927 Cd Length: 59 Bit Score: 121.58 E-value: 8.47e-33

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 688602146 1001 IAQVTTVSPATTPEQLSLTPGQLIVVLHKNSNSWWLGELQARGKKRKKGWFQSSNVRLL 1059
Cdd:cd11994     1 IAQVTTAYVASGVEQLSLSPGQLILILKKNSSGWWLGELQARGKKRQKGWFPASHVKLL 59

First Src homology 3 domain (or SH3A) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The first SH3 domain (or SH3A) of ITSN2 is expected to bind many protein partners, similar to ITSN1 which has been shown to bind Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212921 [Multi-domain] Cd Length: 57 Bit Score: 120.75 E-value: 1.41e-32

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  749 LTTYRALYPFTARNSDELTLEADCFIQVDESTVRETGWLYGSYSGNRGWFPESYAER 805
Cdd:cd11988     1 LVNYRALYPFEARNHDEMSFNAGDIIQVDEKTVGEPGWLYGSFQGNFGWFPCNYVEK 57

Fifth Src homology 3 domain (or SH3E) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212929 [Multi-domain] Cd Length: 54 Bit Score: 112.77 E-value: 8.09e-30

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1074 CQVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11996     1 CQVIAMYDYTANNEDELSFSKGQLINVLNKDDPDWWQGEINGVTGLFPSNYVKM 54

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

Pssm-ID: 197477 [Multi-domain] Cd Length: 96 Bit Score: 113.14 E-value: 1.81e-29

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146    214 DWAVPQSSRLKYRQLFNSLDKLMSGYLSGPQVRNALTASNLTQTQLATIWFLADVDRDGQLRAEEFILAMHLVEMAKTGR 293
Cdd:smart00027    1 PWAISPEDKAKYEQIFRSLDKNQDGTVTGAQAKPILLKSGLPQTLLAKIWNLADIDNDGELDKDEFALAMHLIYRKLNGY 80

Third Src homology 3 domain (or SH3C) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. The SH3C of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212772 [Multi-domain] Cd Length: 52 Bit Score: 110.97 E-value: 3.48e-29

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEKEGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11838     1 EYIALYPYESNEPGDLTFNAGDVILVTKKDGEWWTGTIGDRTGIFPSNYVRP 52

Fifth Src homology 3 domain (or SH3E) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212774 [Multi-domain] Cd Length: 53 Bit Score: 107.50 E-value: 4.93e-28

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11840     1 QVIALFPYTAQNEDELSFQKGDIINVLSKDDPDWWRGELNGQTGLFPSNYVEP 53

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

Pssm-ID: 238009 [Multi-domain] Cd Length: 67 Bit Score: 97.68 E-value: 2.26e-24

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146   19 DKQFDSLAPT-LGYLSGDQARKFFLQSGLPTSVLADIWALADIGKDGKMDRLEFSIAMKLIKLQLQ 83
Cdd:cd00052     2 DQIFRSLDPDgDGLISGDEARPFLGKSGLPRSVLAQIWDLADTDKDGKLDKEEFAIAMHLIALALN 67

Fifth Src homology 3 domain (or SH3E) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212928 [Multi-domain] Cd Length: 54 Bit Score: 96.56 E-value: 3.66e-24

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1074 CQVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11995     1 CQVIGMYDYTAQNDDELAFSKGQIINVLNKEDPDWWKGELNGQVGLFPSNYVKL 54

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

Pssm-ID: 238009 [Multi-domain] Cd Length: 67 Bit Score: 96.13 E-value: 8.18e-24

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  225 YRQLFNSLDKLMSGYLSGPQVRNALTASNLTQTQLATIWFLADVDRDGQLRAEEFILAMHLVEMAKT 291
Cdd:cd00052     1 YDQIFRSLDPDGDGLISGDEARPFLGKSGLPRSVLAQIWDLADTDKDGKLDKEEFAIAMHLIALALN 67

Third Src homology 3 domain (or SH3C) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212924 Cd Length: 52 Bit Score: 93.12 E-value: 6.51e-23

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEKEGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11991     1 EYVAMYTYESNEQGDLTFQQGDVILVTKKDGDWWTGTVGDKTGVFPSNYVRP 52

Third Src homology 3 domain (or SH3C) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (SH3C) of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212925 Cd Length: 52 Bit Score: 92.77 E-value: 9.61e-23

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEKEGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11992     1 EYIALYPYSSSEPGDLTFNEGEEILVTQKDGEWWTGSIEDRTGIFPSNYVRP 52

Second Src homology 3 domain (or SH3B) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212923 [Multi-domain] Cd Length: 52 Bit Score: 92.03 E-value: 1.59e-22

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11990     1 KAQALCSWTAKKDNHLNFSKNDIITVLEQQENWWFGEVHGGRGWFPKSYVKL 52

C2 domain; The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 175973 [Multi-domain] Cd Length: 102 Bit Score: 92.52 E-value: 3.76e-22

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1513 LLVTVLEATELKPCKPNGKSNPYCELTMG-AQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQFSPDDFLG 1591
Cdd:cd00030     1 LRVTVIEARNLPAKDLNGKSDPYVKVSLGgKQKFKTKVVKNTLNPVWNETFEFPVLDPESDTLTVEVWDKDRFSKDDFLG 80

                          90
                  ....*....|..
gi 688602146 1592 RTEVPVATIKKD 1603
Cdd:cd00030    81 EVEIPLSELLDS 92

Fourth Src homology 3 domain (or SH3D) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212926 Cd Length: 65 Bit Score: 89.41 E-value: 1.85e-21

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 688602146  997 KKPEIAQVTTVSPATTPEQLSLTPGQLIVVLHKNSNSWWLGELQARGKKRKKGWFQSSNVRLL 1059
Cdd:cd11993     1 KKPEIAQVIASYTATGPEQLTLAPGQLILIRKKNPGGWWEGELQARGKKRQIGWFPANYVKLL 63

First Src homology 3 domain (or SH3A) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212770 [Multi-domain] Cd Length: 55 Bit Score: 88.18 E-value: 4.02e-21

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTVRETGWLYGSYSGNRGWFPESYAER 805
Cdd:cd11836     2 YRALYAFEARNPDEISFQPGDIIQVDESQVAEPGWLAGELKGKTGWFPANYVEK 55

C2 domain;

Pssm-ID: 425499 [Multi-domain] Cd Length: 104 Bit Score: 89.69 E-value: 4.30e-21

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  1511 GRLLVTVLEATELKPCKPNGKSNPYCELTM--GAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQFSPDD 1588
Cdd:pfam00168    1 GRLTVTVIEAKNLPPKDGNGTSDPYVKVYLldGKQKKKTKVVKNTLNPVWNETFTFSVPDPENAVLEIEVYDYDRFGRDD 80

                           90
                   ....*....|....*.
gi 688602146  1589 FLGRTEVPVATIKKDQ 1604
Cdd:pfam00168   81 FIGEVRIPLSELDSGE 96

Fourth Src homology 3 domain (or SH3D) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212773 [Multi-domain] Cd Length: 58 Bit Score: 87.78 E-value: 5.69e-21

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 688602146 1001 IAQVTTVSPATTPEQLSLTPGQLIVVLHKNSNSWWLGELQARGKKRKKGWFQSSNVRL 1058
Cdd:cd11839     1 IAQVIAPFTATAENQLSLAVGQLVLVRKKSPSGWWEGELQARGKKRQIGWFPANYVKL 58

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

Pssm-ID: 214620 [Multi-domain] Cd Length: 56 Bit Score: 86.82 E-value: 1.12e-20

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146   1072 PLCQVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEV-AGVTGLFPTNYVK 1126
Cdd:smart00326    1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLgRGKEGLFPSNYVE 56

Protein kinase C conserved region 2 (CalB); Ca2+-binding motif present in phospholipases, protein kinases C, and synaptotagmins (among others). Some do not appear to contain Ca2+-binding sites. Particular C2s appear to bind phospholipids, inositol polyphosphates, and intracellular proteins. Unusual occurrence in perforin. Synaptotagmin and PLC C2s are permuted in sequence with respect to N- and C-terminal beta strands. SMART detects C2 domains using one or both of two profiles.

Pssm-ID: 214577 [Multi-domain] Cd Length: 101 Bit Score: 84.85 E-value: 1.92e-19

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   1512 RLLVTVLEATELKPCKPNGKSNPYCELTMG---AQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQFSPDD 1588
Cdd:smart00239    1 TLTVKIISARNLPPKDKGGKSDPYVKVSLDgdpKEKKKTKVVKNTLNPVWNETFEFEVPPPELAELEIEVYDKDRFGRDD 80

                            90
                    ....*....|....*.
gi 688602146   1589 FLGRTEVPVATIKKDQ 1604
Cdd:smart00239   81 FIGQVTIPLSDLLLGG 96

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

Pssm-ID: 212690 [Multi-domain] Cd Length: 51 Bit Score: 79.81 E-value: 2.76e-18

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVA-GVTGLFPTNY 1124
Cdd:cd00174     1 YARALYDYEAQDDDELSFKKGDIITVLEKDDDGWWEGELNgGREGLFPANY 51

Second Src homology 3 domain (or SH3B) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212771 [Multi-domain] Cd Length: 53 Bit Score: 78.56 E-value: 7.66e-18

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQENWWYGELKE-KRGWFPCSHVS 904
Cdd:cd11837     1 TATALYPWRAKKENHLSFAKGDIITVLEQQEMWWFGELEGgEEGWFPKSYVK 52

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The C-terminal SH3 domains (SH3c) of GRB2 and GRAP2 have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212739 [Multi-domain] Cd Length: 53 Bit Score: 73.43 E-value: 5.26e-16

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11805     1 RVQALYDFNPQEPGELEFRRGDIITVLDSSDPDWWKGELRGRVGIFPANYVQ 52

First Src homology 3 domain (or SH3A) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212920 [Multi-domain] Cd Length: 55 Bit Score: 73.49 E-value: 5.65e-16

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTVRETGWLYGSYSGNRGWFPESYAER 805
Cdd:cd11987     2 YRALYPFEARSHDEITIQPGDIVMVDESQTGEPGWLGGELKGKTGWFPANYAEK 55

Src homology 3 domain of Abl Interactor proteins; Abl interactor (Abi) proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. They localize to sites of actin polymerization in epithelial adherens junction and immune synapses, as well as to the leading edge of lamellipodia. Vertebrates contain two Abi proteins, Abi1 and Abi2. Abi1 displays a wide expression pattern while Abi2 is highly expressed in the eye and brain. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212760 [Multi-domain] Cd Length: 52 Bit Score: 72.74 E-value: 8.64e-16

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11826     2 VVALYDYTADKDDELSFQEGDIIYVTKKNDDGWYEGVLNGVTGLFPGNYV 51

Variant SH3 domain;

Pssm-ID: 434066 [Multi-domain] Cd Length: 49 Bit Score: 71.88 E-value: 1.52e-15

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 688602146  1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:pfam14604    1 ALYPYEPKDDDELSLQRGDVITVIEESEDGWWEGINTGRTGLVPANYVE 49

Second Src homology 3 domain (or SH3B) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212922 [Multi-domain] Cd Length: 52 Bit Score: 72.05 E-value: 1.59e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11989     1 QAQALYPWRAKKDNHLNFNKNDVITVLEQQDMWWFGEVQGQKGWFPKSYVKL 52

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212808 [Multi-domain] Cd Length: 55 Bit Score: 72.00 E-value: 1.96e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPD--WWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11875     4 VLFDYEAENEDELTLREGDIVTILSKDCEDkgWWKGELNGKRGVFPDNFVE 54

Src homology 3 domain of Signal Transducing Adaptor Molecule 1; STAM1 is part of the endosomal sorting complex required for transport (ESCRT-0) and is involved in sorting ubiquitinated cargo proteins from the endosome. It may also be involved in the regulation of IL2 and GM-CSF mediated signaling, and has been implicated in neural cell survival. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212897 [Multi-domain] Cd Length: 55 Bit Score: 71.52 E-value: 2.55e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11964     2 KVRAIYDFEAAEDNELTFKAGDIITILDDSDPNWWKGETPQGTGLFPSNFV 52

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

Pssm-ID: 214620 [Multi-domain] Cd Length: 56 Bit Score: 69.87 E-value: 8.60e-15

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 688602146    934 YVALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRG-CIGDQTGLFPSNYVK 983
Cdd:smart00326    5 VRALYDYTAQDPDELSFKKGDIITVLEKsDDGWWKGrLGRGKEGLFPSNYVE 56

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212746 [Multi-domain] Cd Length: 52 Bit Score: 69.46 E-value: 1.46e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGE-VAGVTGLFPTNYV 1125
Cdd:cd11812     2 VVALYDYTANRSDELTIHRGDIIRVLYKDNDNWWFGSlVNGQQGYFPANYV 52

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 394975 [Multi-domain] Cd Length: 47 Bit Score: 69.15 E-value: 1.56e-14

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 688602146  1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEV-AGVTGLFPT 1122
Cdd:pfam00018    1 VALYDYTAQEPDELSFKKGDIIIVLEKSEDGWWKGRNkGGKEGLIPS 47

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212754 [Multi-domain] Cd Length: 54 Bit Score: 68.65 E-value: 2.63e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11820     2 KVRALYDFEAAEDNELTFKAGEIITVLDDSDPNWWKGSNHRGEGLFPANFVT 53

C2 domain first and third repeat in Synaptotagmin-like proteins; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains either the first or third repeat in Synaptotagmin-like proteins with a type-I topology.

Pssm-ID: 176037 [Multi-domain] Cd Length: 121 Bit Score: 70.40 E-value: 3.49e-14

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKpCKPN-------GKSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQ 1583
Cdd:cd08391     1 GVLRIHVIEAQDLV-AKDKfvgglvkGKSDPYVIVRVGAQTFKSKVIKENLNPKWNEVYEAVVDEVPGQELEIELFDEDP 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 688602146 1584 fSPDDFLGRTEVPVATIKKdqdgKGPLVRRLLLHEVPTGEVKVRL 1628
Cdd:cd08391    80 -DKDDFLGRLSIDLGSVEK----KGFIDEWLPLEDVKSGRLHLKL 119

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 429575 [Multi-domain] Cd Length: 54 Bit Score: 68.39 E-value: 3.59e-14

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:pfam07653    2 GRVIFDYVGTDKNGLTLKKGDVVKVLGKDNDGWWEGETGGRVGLVPSTAVE 52

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the Saccharomyces cerevisiae proteins, Ysc84p (also called LAS17-binding protein 4, Lsb4p) and Lsb3p, and similar fungal proteins. They contain an N-terminal SYLF domain (also called DUF500) and a C-terminal SH3 domain. Ysc84p localizes to actin patches and plays an important in actin polymerization during endocytosis. The N-terminal domain of both Ysc84p and Lsb3p can bind and bundle actin filaments. A study of the yeast SH3 domain interactome predicts that the SH3 domains of Lsb3p and Lsb4p may function as molecular hubs for the assembly of endocytic complexes. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212776 [Multi-domain] Cd Length: 55 Bit Score: 67.83 E-value: 5.34e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNP--DWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11842     1 KAVALYDFAGEQPGDLAFQKGDIITILKKSDSqnDWWTGRIGGREGIFPANYVE 54

C-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domains (SH3c) of the related proteins, GRB2 and GRAP2, have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212884 Cd Length: 53 Bit Score: 66.75 E-value: 1.03e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11951     2 VQAQYDFSAEDPSQLSFRRGDIIEVLDCPDPNWWRGRISGRVGFFPRNYV 51

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or SH3P2, is a signaling protein containing SH3 and ankyrin-repeat domains. It acts through a Src-related pathway to enhance the formation of osteoclasts and bone resorption. It also acts as a negative regulator of cell motility. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212706 [Multi-domain] Cd Length: 53 Bit Score: 66.55 E-value: 1.45e-13

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11772     4 ALYDYEAQHPDELSFEEGDLLYISDKSDPNWWKATCGGKTGLIPSNYV 51

C-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also has roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRAP2 binds to different motifs found in substrate peptides including the typical PxxP motif in hematopoietic progenitor kinase 1 (HPK1), the RxxK motif in SLP-76 and HPK1, and the RxxxxK motif in phosphatase-like protein HD-PTP. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212883 [Multi-domain] Cd Length: 53 Bit Score: 66.39 E-value: 1.58e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11950     1 QVRALYDFEALEDDELGFNSGDVIEVLDSSNPSWWKGRLHGKLGLFPANYVA 52

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

Pssm-ID: 214620 [Multi-domain] Cd Length: 56 Bit Score: 66.41 E-value: 1.70e-13

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 688602146    854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELK-EKRGWFPCSHV 903
Cdd:smart00326    4 QVRALYDYTAQDPDELSFKKGDIITVLEKSDdGWWKGRLGrGKEGLFPSNYV 55

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212757 [Multi-domain] Cd Length: 53 Bit Score: 66.21 E-value: 2.12e-13

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11823     4 ALYSYTANREDELSLQPGDIIEVHEKQDDGWWLGELNGKKGIFPATYV 51

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

Pssm-ID: 212690 [Multi-domain] Cd Length: 51 Bit Score: 65.95 E-value: 2.43e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRG-CIGDQTGLFPSNY 981
Cdd:cd00174     2 ARALYDYEAQDDDELSFKKGDIITVLEKdDDGWWEGeLNGGREGLFPANY 51

Third Src homology 3 domain (or SH3C) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212924 Cd Length: 52 Bit Score: 65.39 E-value: 3.10e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNpDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11991     1 EYVAMYTYESNEQGDLTFQQGDVILVTKKDG-DWWTGTVGDKTGVFPSNYVRP 52

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The N-terminal SH3 domain of GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212738 [Multi-domain] Cd Length: 52 Bit Score: 65.46 E-value: 3.24e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKD-NPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11804     3 VAKHDFKATAEDELSFKKGSILKVLNMEdDPNWYKAELDGKEGLIPKNYI 52

Cytoskeletal-regulatory complex EF hand; This is an efhand family from the N-terminal of actin cytoskeleton-regulatory complex END3 and similar proteins from fungi and closely related species.

Pssm-ID: 289529 Cd Length: 104 Bit Score: 67.40 E-value: 3.33e-13

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146    10 ITPEERGKHDKQFDSLAPTLGYLSGDQARKFFLQSGLPTSVLADIWALADIGKDGKMDRLEFSIAMKLIKLQLQG--QPL 87
Cdd:pfam12763    4 LEEWEIKKYWEIFSGLKPENNKLTGDQVSPVLKNSRLPDDQLAKIWDLADIDSDGKLDFEEFCIAMRLIFDLVNGniADV 83


                   ....*
gi 688602146    88 PSSLP 92
Cdd:pfam12763   84 PDELP 88

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212810 [Multi-domain] Cd Length: 53 Bit Score: 65.41 E-value: 3.43e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11877     1 LVRAKFNFEGTNEDELSFDKGDIITVTQVVEGGWWEGTLNGKTGWFPSNYVK 52

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If (MyoIf) are nonmuscle, unconventional, long tailed, class I myosins containing an N-terminal motor domain and a myosin tail with TH1, TH2, and SH3 domains. MyoIe interacts with the endocytic proteins, dynamin and synaptojanin-1, through its SH3 domain; it may play a role in clathrin-dependent endocytosis. In the kidney, MyoIe is critical for podocyte function and normal glomerular filtration. Mutations in MyoIe is associated with focal segmental glomerulosclerosis, a disease characterized by massive proteinuria and progression to end-stage kidney disease. MyoIf is predominantly expressed in the immune system; it plays a role in immune cell motility and innate immunity. Mutations in MyoIf may be associated with the loss of hearing. The MyoIf gene has also been found to be fused to the MLL (Mixed lineage leukemia) gene in infant acute myeloid leukemias (AML). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212761 [Multi-domain] Cd Length: 53 Bit Score: 64.74 E-value: 5.75e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11827     1 QCKALYAYDAQDTDELSFNEGDIIEILKEDPSGWWTGRLRGKEGLFPGNYV 51

Src homology 3 domain of Signal Transducing Adaptor Molecule 2; STAM2, also called EAST (Epidermal growth factor receptor-associated protein with SH3 and TAM domain) or Hbp (Hrs binding protein), is part of the endosomal sorting complex required for transport (ESCRT-0). It plays a role in sorting mono-ubiquinated endosomal cargo for trafficking to the lysosome for degradation. It is also involved in the regulation of exocytosis. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212896 [Multi-domain] Cd Length: 57 Bit Score: 65.04 E-value: 6.25e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11963     3 KVRALYDFEAVEDNELTFKHGEIIIVLDDSDANWWKGENHRGVGLFPSNFV 53

Src homology 3 domain of Abl Interactor 2; Abi2 is highly expressed in the brain and eye. It regulates actin cytoskeletal reorganization at adherens junctions and dendritic spines, which is important in cell morphogenesis, migration, and cognitive function. Mice deficient with Abi2 show defects in orientation and migration of lens fibers, neuronal migration, dendritic spine morphology, as well as deficits in learning and memory. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212905 [Multi-domain] Cd Length: 61 Bit Score: 65.03 E-value: 6.59e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1073 LCQVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11972     2 LEKVVAIYDYTKDKEDELSFQEGAIIYVIKKNDDGWYEGVMNGVTGLFPGNYVE 55

Src homology 3 domain of Cortactin; Cortactin was originally identified as a substrate of Src kinase. It is an actin regulatory protein that binds to the Arp2/3 complex and stabilizes branched actin filaments. It is involved in cellular processes that affect cell motility, adhesion, migration, endocytosis, and invasion. It is expressed ubiquitously except in hematopoietic cells, where the homolog hematopoietic lineage cell-specific 1 (HS1) is expressed instead. Cortactin contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region interacts with the Arp2/3 complex and F-actin, and is crucial in regulating branched actin assembly. Cortactin also serves as a scaffold and provides a bridge to the actin cytoskeleton for membrane trafficking and signaling proteins that bind to its SH3 domain. Binding partners for the SH3 domain of cortactin include dynamin2, N-WASp, MIM, FGD1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212892 [Multi-domain] Cd Length: 53 Bit Score: 64.75 E-value: 6.77e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11959     3 VALYDYQAADDDEISFDPDDIITNIEMIDEGWWRGVCRGKYGLFPANYVEL 53

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; N-terminal SH3 domain of the uncharacterized protein SH3 domain-containing protein 21, and similar uncharacterized domains, it belongs to the CD2AP-like_3 subfamily of proteins. The CD2AP-like_3 subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213018 [Multi-domain] Cd Length: 55 Bit Score: 64.02 E-value: 1.24e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146 1074 CQViaMYDYKAANKDEMSFQKGQLITVLNKDNPD--WWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd12142     2 CRV--LFDYNPVAPDELALKKGDVIEVISKETEDegWWEGELNGRRGFFPDNFVMP 55

C2 domain fourth repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the fifth C2 repeat, C2E, and has a type-II topology.

Pssm-ID: 176005 [Multi-domain] Cd Length: 115 Bit Score: 66.05 E-value: 1.30e-12

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1513 LLVTVLEATELKPCKPNGKSNPYCELTM-GAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQFSPDDFLG 1591
Cdd:cd04040     1 LTVDVISAENLPSADRNGKSDPFVKFYLnGEKVFKTKTIKKTLNPVWNESFEVPVPSRVRAVLKVEVYDWDRGGKDDLLG 80


                  ....*....
gi 688602146 1592 RTEVPVATI 1600
Cdd:cd04040    81 SAYIDLSDL 89

C-terminal (or second) Src Homology 3 domain of the p67phox subunit of NADPH oxidase; p67phox, also called Neutrophil cytosol factor 2 (NCF-2), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox plays a regulatory role and contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. It binds, via its C-terminal SH3 domain, to a proline-rich region of p47phox and upon activation, this complex assembles with flavocytochrome b558, the Nox2-p22phox heterodimer. Concurrently, RacGTP translocates to the membrane and interacts with the TPR domain of p67phox, which leads to the activation of NADPH oxidase. The PB1 domain of p67phox binds to its partner PB1 domain in p40phox, and this facilitates the assembly of p47phox-p67phox at the membrane. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212979 [Multi-domain] Cd Length: 53 Bit Score: 63.67 E-value: 1.32e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12046     1 QVVALFSYEASQPEDLEFQKGDVILVLSKVNEDWLEGQCKGKIGIFPSAFVE 52

Src homology 3 domain of Phospholipase C (PLC) gamma; PLC catalyzes the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG) in response to various receptors. Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma catalyzes this reaction in tyrosine kinase-dependent signaling pathways. It is activated and recruited to its substrate at the membrane. Vertebrates contain two forms of PLCgamma, PLCgamma1, which is widely expressed, and PLCgamma2, which is primarily found in haematopoietic cells. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212759 [Multi-domain] Cd Length: 54 Bit Score: 63.51 E-value: 1.64e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAG-VTGLFPTNYVK 1126
Cdd:cd11825     2 VKALYDYRAQRPDELSFCKHAIITNVEKEDGGWWRGDYGGkKQKWFPANYVE 53

Src homology 3 domain of Slit-Robo GTPase Activating Protein 4; srGAP4, also called ARHGAP4, is highly expressed in hematopoietic cells and may play a role in lymphocyte differentiation. It is able to stimulate the GTPase activity of Rac1, Cdc42, and RhoA. In the nervous system, srGAP4 has been detected in differentiating neurites and may be involved in axon and dendritic growth. srGAPs are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212889 [Multi-domain] Cd Length: 55 Bit Score: 63.71 E-value: 1.66e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1074 CQVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11956     2 VEAVACFDYTGRTAQELSFKRGDVLLLHSKASSDWWRGEHNGMRGLIPHKYI 53

Src homology 3 domain of Cortactin and related proteins; This subfamily includes cortactin, Abp1 (actin-binding protein 1), hematopoietic lineage cell-specific protein 1 (HS1), and similar proteins. These proteins are involved in regulating actin dynamics through direct or indirect interaction with the Arp2/3 complex, which is required to initiate actin polymerization. They all contain at least one C-terminal SH3 domain. Cortactin and HS1 bind Arp2/3 and actin through an N-terminal region that contains an acidic domain and several copies of a repeat domain found in cortactin and HS1. Abp1 binds actin via an N-terminal actin-depolymerizing factor (ADF) homology domain. Yeast Abp1 binds Arp2/3 directly through two acidic domains. Mammalian Abp1 does not directly interact with Arp2/3; instead, it regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. The C-terminal region of these proteins acts as an adaptor or scaffold that can connect membrane trafficking and signaling proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212753 [Multi-domain] Cd Length: 54 Bit Score: 63.49 E-value: 1.73e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVA-GVTGLFPTNYVKM 1127
Cdd:cd11819     3 KALYDYQAAEDNEISFVEGDIITQIEQIDEGWWLGVNAkGQKGLFPANYVEL 54

N-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The N-terminal SH3 domain of the related protein GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212881 [Multi-domain] Cd Length: 54 Bit Score: 62.91 E-value: 2.46e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLN-KDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11948     1 EAVALYSFQATESDELPFQKGDILKILNmEDDQNWYKAELQGREGYIPKNYIKV 54

Cytoskeletal-regulatory complex EF hand; This is an efhand family from the N-terminal of actin cytoskeleton-regulatory complex END3 and similar proteins from fungi and closely related species.

Pssm-ID: 289529 Cd Length: 104 Bit Score: 64.70 E-value: 2.52e-12

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 688602146   224 KYRQLFNSLdKLMSGYLSGPQVRNALTASNLTQTQLATIWFLADVDRDGQLRAEEFILAMHLV 286
Cdd:pfam12763   11 KYWEIFSGL-KPENNKLTGDQVSPVLKNSRLPDDQLAKIWDLADIDSDGKLDFEEFCIAMRLI 72

C2 domain first repeat present in Synaptotagmin-like proteins; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

Pssm-ID: 175990 [Multi-domain] Cd Length: 128 Bit Score: 65.52 E-value: 2.78e-12

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATEL--KPCKPNGKSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQFSPDD 1588
Cdd:cd04024     1 GVLRVHVVEAKDLaaKDRSGKGKSDPYAILSVGAQRFKTQTIPNTLNPKWNYWCEFPIFSAQNQLLKLILWDKDRFAGKD 80

                          90
                  ....*....|....*
gi 688602146 1589 FLGRTEVPVATIKKD 1603
Cdd:cd04024    81 YLGEFDIALEEVFAD 95

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212700 [Multi-domain] Cd Length: 53 Bit Score: 62.67 E-value: 2.92e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11766     1 PAVVKFNYEAQREDELSLRKGDRVLVLEKSSDGWWRGECNGQVGWFPSNYV 51

Fifth Src homology 3 domain (or SH3E) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212774 [Multi-domain] Cd Length: 53 Bit Score: 62.82 E-value: 2.93e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKE-GEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11840     3 IALFPYTAQNEDELSFQKGDIINVLSKDdPDWWRGELNGQTGLFPSNYVEP 53

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

Pssm-ID: 227709 [Multi-domain] Cd Length: 1175 Bit Score: 71.85 E-value: 3.57e-12

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1145 DSMCTEERKRQGYIHELIQTEESYLEDLELAVEVFYKPMAESGRLTEAE----ISMIFVNWRELIMCSTKLLKALRVRKK 1220
Cdd:COG5422   476 ESLPKQEIKRQEAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPENArrnfIKHVFANINEIYAVNSKLLKALTNRQC 555

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1221 TAGermPVQVVGDILSSELSHMQAYIRFCSCQLNAAALLQQKTDKSLDFKLFLKKIASNYRCKGMPLSSFLLKPMQRITR 1300
Cdd:COG5422   556 LSP---IVNGIADIFLDYVPKFEPFIKYGASQPYAKYEFEREKSVNPNFARFDHEVERLDESRKLELDGYLTKPTTRLAR 632

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1301 YPLLIKNILENTPPAHADHSNLQAALEQAEELCSQVNEAVREKENSDRLEWIQNHVLCDGVIEHLVFNSLTnclgpRKLL 1380
Cdd:COG5422   633 YPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESGKAENRGDLFHLNQQLLFKPEYVNLGLNDEY-----RKII 707

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1381 HSGKLHKTKSSK-------ELWALLFNDFLLLTYTSKQFSSSPDKLFNPNSNTQYkMYKTPVFLNEVLVKMPSDPSSD-- 1451
Cdd:COG5422   708 FKGVLKRKAKSKtdgslrgDIQFFLLDNMLLFCKAKAVNKWRQHKVFQRPIPLEL-LFISPDEDSPDRAEYLKPAPSAdv 786

                         330       340       350       360
                  ....*....|....*....|....*....|....*....|....*
gi 688602146 1452 -DPVFHISHIDRVY-------------TLKTDTINERTTWVQKIK 1482
Cdd:COG5422   787 lDPAYNTKPPKNAYgfelygngqryqiTLYAETHAGRDTWLEHIK 831

Third Src Homology 3 domain (SH3C) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CIN85. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212990 [Multi-domain] Cd Length: 56 Bit Score: 62.61 E-value: 4.07e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146 1074 CQVIamYDYKAANKDEMSFQKGQLITVLNKDNPD--WWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd12057     2 CKVL--FPYEAQNEDELTIKEGDIVTLISKDCIDagWWEGELNGRRGVFPDNFVKL 55

First Src Homology 3 domain (SH3A) of CD2-associated protein and similar proteins; This subfamily is composed of the first SH3 domain (SH3A) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3A of both proteins bind to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic domain of the cell adhesion protein CD2. CIN85 SH3A binds to internal proline-rich motifs within the proline-rich region; this intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. CIN85 SH3A has also been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212806 [Multi-domain] Cd Length: 53 Bit Score: 62.28 E-value: 4.11e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11873     2 VIVEFDYDAEEPDELTLKVGDIITNVKKMEEGWWEGTLNGKRGMFPDNFVK 52

Src homology 3 domain of Hematopoietic lineage cell-specific protein 1; HS1, also called HCLS1 (hematopoietic cell-specific Lyn substrate 1), is a cortactin homolog expressed specifically in hematopoietic cells. It is an actin regulatory protein that binds the Arp2/3 complex and stabilizes branched actin filaments. It is required for cell spreading and signaling in lymphocytes. It regulates cytoskeletal remodeling that controls lymphocyte trafficking, and it also affects tissue invasion and infiltration of leukemic B cells. Like cortactin, HS1 contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region binds the Arp2/3 complex and F-actin, while the C-terminal region acts as an adaptor or scaffold that can connect varied proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213006 [Multi-domain] Cd Length: 55 Bit Score: 62.16 E-value: 4.95e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKMT 1128
Cdd:cd12073     4 VALYDYQGEGDDEISFDPQETITDIEMVDEGWWKGTCHGHRGLFPANYVELL 55

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212882 [Multi-domain] Cd Length: 53 Bit Score: 62.16 E-value: 5.37e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11949     2 VQALFDFDPQEDGELGFRRGDFIEVMDNSDPNWWKGACHGQTGMFPRNYVT 52

Second C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212894 [Multi-domain] Cd Length: 53 Bit Score: 61.77 E-value: 5.89e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11961     2 AKALYDYDAAEDNELSFFENDKIINIEFVDDDWWLGECHGSRGLFPSNYVEL 53

Src homology 3 domain of Slit-Robo GTPase Activating Proteins; Slit-Robo GTPase Activating Proteins (srGAPs) are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. Vertebrates contain three isoforms of srGAPs (srGAP1-3), all of which are expressed during embryonic and early development in the nervous system but with different localization and timing. A fourth member has also been reported (srGAP4, also called ARHGAP4). srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212743 [Multi-domain] Cd Length: 53 Bit Score: 61.65 E-value: 6.73e-12

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11809     3 TAQFDYTGRSERELSFKKGDSLTLYRQVSDDWWRGQLNGQDGLVPHKYI 51

Src homology 3 domain of Src kinase-like Protein Tyrosine Kinases; Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, Yes, and Brk. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Src kinases are overexpressed in a variety of human cancers, making them attractive targets for therapy. They are also implicated in acute inflammatory responses and osteoclast function. Src, Fyn, Yes, and Yrk are widely expressed, while Blk, Lck, Hck, Fgr, Lyn, and Brk show a limited expression pattern. This subfamily also includes Drosophila Src42A, Src oncogene at 42A (also known as Dsrc41) which accumulates at sites of cell-cell or cell-matrix adhesion, and participates in Drosphila development and wound healing. It has been shown to promote tube elongation in the tracheal system, is essential for proper cell-cell matching during dorsal closure, and regulates cell-cell contacts in developing Drosophila eyes. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212779 [Multi-domain] Cd Length: 52 Bit Score: 61.44 E-value: 8.50e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGE--VAGVTGLFPTNY 1124
Cdd:cd11845     1 IYVALYDYEARTDDDLSFKKGDRLQILDDSDGDWWLARhlSTGKEGYIPSNY 52

Src homology 3 domain of SH3 domain containing Ysc84-like 1 (SH3YL1) protein; SH3YL1 localizes to the plasma membrane and is required for dorsal ruffle formation. It binds phosphoinositides (PIs) with high affinity through its N-terminal SYLF domain (also called DUF500). In addition, SH3YL1 contains a C-terminal SH3 domain which has been reported to bind to N-WASP, dynamin 2, and SHIP2 (a PI 5-phosphatase). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212775 Cd Length: 54 Bit Score: 61.25 E-value: 9.98e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLV---TEKEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11841     4 ALYSFEGQQPCDLSFQAGDRITVltrTDSQFDWWEGRLRGRVGIFPANYVS 54

Second Src homology 3 domain (or SH3B) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212771 [Multi-domain] Cd Length: 53 Bit Score: 61.23 E-value: 1.08e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNpDWWKGEV-AGVTGLFPTNYVKM 1127
Cdd:cd11837     1 TATALYPWRAKKENHLSFAKGDIITVLEQQE-MWWFGELeGGEEGWFPKSYVKE 53

First Src Homology 3 domain (SH3A) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CIN85; SH3A binds to internal proline-rich motifs within the proline-rich region. This intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. SH3A has also been shown to bind ubiquitin and to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic end of the cell adhesion protein CD2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212985 [Multi-domain] Cd Length: 53 Bit Score: 61.06 E-value: 1.20e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12052     1 EAIVEFDYKAQHEDELTITVGDIITKIKKDDGGWWEGEIKGRRGLFPDNFVR 52

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

Pssm-ID: 212690 [Multi-domain] Cd Length: 51 Bit Score: 60.94 E-value: 1.36e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQ-ENWWYGELKE-KRGWFPCSH 902
Cdd:cd00174     1 YARALYDYEAQDDDELSFKKGDIITVLEKDdDGWWEGELNGgREGLFPANY 51

Src Homology 3 domain of Mixed Lineage Kinases; MLKs are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Mammals have four MLKs (MLK1-4), mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212809 [Multi-domain] Cd Length: 58 Bit Score: 60.60 E-value: 1.78e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKD-----NPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11876     4 ALFDYDARGEDELTLRRGQPVEVLSKDaavsgDEGWWTGKIGDKVGIFPSNYV 56

C2 domain third repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); MCTPs are involved in Ca2+ signaling at the membrane. The cds in this family contain multiple C2 domains as well as a C-terminal PRT domain. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

Pssm-ID: 176023 [Multi-domain] Cd Length: 119 Bit Score: 62.70 E-value: 2.03e-11

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKPCKPNGKSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLYqDVLCLTVFERDQFSPDDFL 1590
Cdd:cd08377     1 GFLQVKVIRASGLAAADIGGKSDPFCVLELVNARLQTHTIYKTLNPEWNKIFTFPIKDIH-DVLEVTVYDEDKDKKPEFL 79

                          90
                  ....*....|.
gi 688602146 1591 GRTEVPVATIK 1601
Cdd:cd08377    80 GKVAIPLLSIK 90

Third Src homology 3 domain (or SH3C) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. The SH3C of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212772 [Multi-domain] Cd Length: 52 Bit Score: 60.51 E-value: 2.04e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNpDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11838     3 IALYPYESNEPGDLTFNAGDVILVTKKDG-EWWTGTIGDRTGIFPSNYVR 51

Src homology 3 domain of Abl Interactor 1; Abi1, also called e3B1, is a central regulator of actin cytoskeletal reorganization through interactions with many protein complexes. It is part of WAVE, a nucleation-promoting factor complex, that links Rac 1 activation to actin polymerization causing lamellipodia protrusion at the plasma membrane. Abi1 interact with formins to promote protrusions at the leading edge of motile cells. It also is a target of alpha4 integrin, regulating membrane protrusions at sites of integrin engagement. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212904 [Multi-domain] Cd Length: 59 Bit Score: 60.42 E-value: 2.26e-11

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11971     1 KVVAIYDYSKDKDDELSFMEGAIIYVIKKNDDGWYEGVCNGVTGLFPGNYVE 52

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. Its N-terminal SH3 domain binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212879 [Multi-domain] Cd Length: 56 Bit Score: 60.42 E-value: 2.27e-11

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                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKD-NPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11946     2 EAIAKYDFKATADDELSFKRGDILKVLNEEcDQNWYKAELNGKDGFIPKNYIEM 55

Src homology 3 domain of Protein arginine N-methyltransferase 2; PRMT2, also called HRMT1L1, belongs to the arginine methyltransferase protein family. It functions as a coactivator to both estrogen receptor alpha (ER-alpha) and androgen receptor (AR), presumably through arginine methylation. The ER-alpha transcription factor is involved in cell proliferation, differentiation, morphogenesis, and apoptosis, and is also implicated in the development and progression of breast cancer. PRMT2 and its variants are upregulated in breast cancer cells and may be involved in modulating the ER-alpha signaling pathway during formation of breast cancer. PRMT2 also plays a role in regulating the function of E2F transcription factors, which are critical cell cycle regulators, by binding to the retinoblastoma gene product (RB). It contains an N-terminal SH3 domain and an AdoMet binding domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212740 [Multi-domain] Cd Length: 53 Bit Score: 60.10 E-value: 2.39e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11806     2 YVAIADFVATDDSQLSFESGDKLLVLRKPSVDWWWAEHNGCCGYIPASHL 51

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing proteins; ASAPs are Arf GTPase activating proteins (GAPs) and they function in regulating cell growth, migration, and invasion. They contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. Vertebrates contain at least three members, ASAP1, ASAP2, and ASAP3, but some ASAP3 proteins do not seem to harbor a C-terminal SH3 domain. ASAP1 and ASAP2 show GTPase activating protein (GAP) activity towards Arf1 and Arf5. They do not show GAP activity towards Arf6, but are able to mediate Arf6 signaling by binding stably to GTP-Arf6. ASAP3 is an Arf6-specific GAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212755 [Multi-domain] Cd Length: 53 Bit Score: 60.02 E-value: 2.43e-11

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAG---VTGLFPTNY 1124
Cdd:cd11821     2 VRALYDCQADNDDELTFSEGEIIVVTGEEDDEWWEGHIEGdpsRRGVFPVSF 53

Src homology 3 domain of Endophilin-A; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain three endophilin-A isoforms (A1, A2, and A3). Endophilin-A proteins are enriched in the brain and play multiple roles in receptor-mediated endocytosis. They tubulate membranes and regulate calcium influx into neurons to trigger the activation of the endocytic machinery. They are also involved in the sorting of plasma membrane proteins, actin filament assembly, and the uncoating of clathrin-coated vesicles for fusion with endosomes. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212737 [Multi-domain] Cd Length: 55 Bit Score: 60.35 E-value: 2.43e-11

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                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1072 PLCQviAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11803     1 PCCR--ALYDFEPENEGELGFKEGDIITLTNQIDENWYEGMVNGQSGFFPVNYV 52

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or SH3P2, is a signaling protein containing SH3 and ankyrin-repeat domains. It acts through a Src-related pathway to enhance the formation of osteoclasts and bone resorption. It also acts as a negative regulator of cell motility. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212706 [Multi-domain] Cd Length: 53 Bit Score: 60.01 E-value: 2.62e-11

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11772     2 FRALYDYEAQHPDELSFEEGDLLYISDKsDPNWWKATCGGKTGLIPSNYVEE 53

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing protein 3 (Stac3); Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212919 [Multi-domain] Cd Length: 53 Bit Score: 59.92 E-value: 2.67e-11

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                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11986     3 VALYRFKALEKDDLDFHPGERITVIDDSNEEWWRGKIGEKTGYFPMNFI 51

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212790 [Multi-domain] Cd Length: 53 Bit Score: 59.96 E-value: 3.17e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11856     1 SYVAIADYEAQGDDEISLQEGEVVEVLEKNDSGWWYVRKGDKEGWVPASYLE 52

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the Saccharomyces cerevisiae proteins, Ysc84p (also called LAS17-binding protein 4, Lsb4p) and Lsb3p, and similar fungal proteins. They contain an N-terminal SYLF domain (also called DUF500) and a C-terminal SH3 domain. Ysc84p localizes to actin patches and plays an important in actin polymerization during endocytosis. The N-terminal domain of both Ysc84p and Lsb3p can bind and bundle actin filaments. A study of the yeast SH3 domain interactome predicts that the SH3 domains of Lsb3p and Lsb4p may function as molecular hubs for the assembly of endocytic complexes. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212776 [Multi-domain] Cd Length: 55 Bit Score: 59.74 E-value: 3.21e-11

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEG---EWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11842     3 VALYDFAGEQPGDLAFQKGDIITILKKSDsqnDWWTGRIGGREGIFPANYVE 54

C2 domain second repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); MCTPs are involved in Ca2+ signaling at the membrane. MCTP is composed of a variable N-terminal sequence, three C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-II topology.

Pssm-ID: 176022 [Multi-domain] Cd Length: 116 Bit Score: 61.89 E-value: 3.29e-11

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1515 VTVLEATELKPCKPNGKSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQFSPDDFLGRTE 1594
Cdd:cd08376     4 IVLVEGKNLPPMDDNGLSDPYVKFRLGNEKYKSKVCSKTLNPQWLEQFDLHLFDDQSQILEIEVWDKDTGKKDEFIGRCE 83

                          90
                  ....*....|
gi 688602146 1595 VPVATIKKDQ 1604
Cdd:cd08376    84 IDLSALPREQ 93

Src homology 3 domain of SH3 domain containing Ysc84-like 1 (SH3YL1) protein; SH3YL1 localizes to the plasma membrane and is required for dorsal ruffle formation. It binds phosphoinositides (PIs) with high affinity through its N-terminal SYLF domain (also called DUF500). In addition, SH3YL1 contains a C-terminal SH3 domain which has been reported to bind to N-WASP, dynamin 2, and SHIP2 (a PI 5-phosphatase). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212775 Cd Length: 54 Bit Score: 59.71 E-value: 3.35e-11

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                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNP--DWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11841     1 EVTALYSFEGQQPCDLSFQAGDRITVLTRTDSqfDWWEGRLRGRVGIFPANYVS 54

Src homology 3 domain of Alpha Spectrin; Spectrin is a major structural component of the red blood cell membrane skeleton and is important in erythropoiesis and membrane biogenesis. It is a flexible, rope-like molecule composed of two subunits, alpha and beta, which consist of many spectrin-type repeats. Alpha and beta spectrin associate to form heterodimers and tetramers; spectrin tetramer formation is critical for red cell shape and deformability. Defects in alpha spectrin have been associated with inherited hemolytic anemias including hereditary spherocytosis (HSp), hereditary elliptocytosis (HE), and hereditary pyropoikilocytosis (HPP). Alpha spectrin contains a middle SH3 domain and a C-terminal EF-hand binding motif in addition to multiple spectrin repeats. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212742 [Multi-domain] Cd Length: 53 Bit Score: 59.81 E-value: 3.62e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11808     2 VVALYDYQEKSPREVSMKKGDILTLLNSSNKDWWKVEVNDRQGFVPAAYVK 52

Src Homology 3 domain of Mixed Lineage Kinase 4; MLK4 is a Serine/Threonine Kinase (STK), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. MLK4 contains an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212991 [Multi-domain] Cd Length: 58 Bit Score: 59.95 E-value: 3.76e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKD-----NPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd12058     4 ALYDYEASGEDELSLRRGDVVEVLSQDaavsgDDGWWAGKIRHRLGIFPANYV 56

Src homology 3 domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; PSTPIP1, also called CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212758 [Multi-domain] Cd Length: 53 Bit Score: 59.69 E-value: 3.80e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11824     3 SVLYDYTAQEDDELSISKGDVVAVIEKGEDGWWTVERNGQKGLVPGTYLE 52

First Src homology 3 domain (or SH3A) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212770 [Multi-domain] Cd Length: 55 Bit Score: 59.68 E-value: 3.96e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDN--PDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11836     4 ALYAFEARNPDEISFQPGDIIQVDESQVaePGWLAGELKGKTGWFPANYV 53

Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

Pssm-ID: 440809 [Multi-domain] Cd Length: 983 Bit Score: 68.04 E-value: 4.08e-11

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  456 ELQTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRQGQWAELELINQRRDVCITDINSLQLQFDEMQ 535
Cdd:COG1196   236 ELEAELEELEAELEELEAELEELEAELAELEAELEELRLELEELELELEEAQAEEYELLAELARLEQDIARLEERRRELE 315

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  536 RQLNQLGPEKQRLADRLVHFTQNISSplindvkqsvcekdrscrkLKEQLDVLERETTAKLSQMEQYNKEIKELRQKQSQ 615
Cdd:COG1196   316 ERLEELEEELAELEEELEELEEELEE-------------------LEEELEEAEEELEEAEAELAEAEEALLEAEAELAE 376

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  616 QQDVLEQLRRVRSDKLKELQRHRKEEEERKRKKEEEAARQAQLEqERLEQEEAERQRKLAQEREAKLREEQQRQALARLL 695
Cdd:COG1196   377 AEEELEELAEELLEALRAAAELAAQLEELEEAEEALLERLERLE-EELEELEEALAELEEEEEEEEEALEEAAEEEAELE 455


                  ....*
gi 688602146  696 EAQEQ 700
Cdd:COG1196   456 EEEEA 460

Src homology 3 domain of Phospholipase C (PLC) gamma 2; PLCgamma2 is primarily expressed in haematopoietic cells, specifically in B cells. It is activated by tyrosine phosphorylation by B cell receptor (BCR) kinases and is recruited to the plasma membrane where its substrate is located. It is required in pre-BCR signaling and in the maturation of B cells. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212902 Cd Length: 55 Bit Score: 59.47 E-value: 4.11e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAG-VTGLFPTNYVK 1126
Cdd:cd11969     2 VKALYDYRAKRSDELSFCKGALIHNVSKETGGWWKGDYGGkVQHYFPSNYVE 53

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The C-terminal SH3 domains (SH3c) of GRB2 and GRAP2 have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212739 [Multi-domain] Cd Length: 53 Bit Score: 59.56 E-value: 4.20e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11805     4 ALYDFNPQEPGELEFRRGDIITVLDSSDPdWWKGELRGRVGIFPANYVQP 53

Src Homology 3 domain of Sorting Nexin 9 and similar proteins; Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. This subfamily consists of SH3 domain containing SNXs including SNX9, SNX18, SNX33, and similar proteins. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212697 [Multi-domain] Cd Length: 55 Bit Score: 59.65 E-value: 4.60e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPD-WWKGEVA-GVTGLFPTNYV 1125
Cdd:cd11763     1 KVRALYDFDSQPSGELSLRAGEVLTITRQDVGDgWLEGRNSrGEVGLFPSSYV 53

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

Pssm-ID: 274008 [Multi-domain] Cd Length: 1179 Bit Score: 68.16 E-value: 4.75e-11

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   452 SKRVELQTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSkrqgqwaELELINQRRDVCITDINSLQLQF 531
Cdd:TIGR02168  253 EELEELTAELQELEEKLEELRLEVSELEEEIEELQKELYALANEISRLEQ-------QKQILRERLANLERQLEELEAQL 325

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   532 DEMQRQLNQLGPEKQRLADRLVHFTQNI---SSPLINDVKQSVCEKDRScRKLKEQLDVLERETTAKLSQMEQYNKEIKE 608
Cdd:TIGR02168  326 EELESKLDELAEELAELEEKLEELKEELeslEAELEELEAELEELESRL-EELEEQLETLRSKVAQLELQIASLNNEIER 404

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   609 LRQKQSQQQDVLEQLRRVRSDKLKELQRHRKEEEERKRKKEEEAARQAQLEQERLEQEEAERQ---RKLAQEREAKLREE 685
Cdd:TIGR02168  405 LEARLERLEDRRERLQQEIEELLKKLEEAELKELQAELEELEEELEELQEELERLEEALEELReelEEAEQALDAAEREL 484

                          250
                   ....*....|....*
gi 688602146   686 QQRQALARLLEAQEQ 700
Cdd:TIGR02168  485 AQLQARLDSLERLQE 499

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212777 [Multi-domain] Cd Length: 53 Bit Score: 59.36 E-value: 4.88e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVL-NKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11843     2 VRALYDYEGQESDELSFKAGDILTKLeEEDEQGWCKGRLDGRVGLYPANYV 52

C2 domain present in Arf GTPase Activating Proteins (GAP); ArfGAP is a GTPase activating protein which regulates the ADP ribosylation factor Arf, a member of the Ras superfamily of GTP-binding proteins. The GTP-bound form of Arf is involved in Golgi morphology and is involved in recruiting coat proteins. ArfGAP is responsible for the GDP-bound form of Arf which is necessary for uncoating the membrane and allowing the Golgi to fuse with an acceptor compartment. These proteins contain an N-terminal ArfGAP domain containing the characteristic zinc finger motif (Cys-x2-Cys-x(16,17)-x2-Cys) and C-terminal C2 domain. C2 domains were first identified in Protein Kinase C (PKC). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 176003 [Multi-domain] Cd Length: 145 Bit Score: 61.96 E-value: 5.95e-11

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1510 IGRLLVTVLEATELKPCKPNGkSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLyQDVLCLTVFERDQFSPDDF 1589
Cdd:cd04038     1 LGLLKVRVVRGTNLAVRDFTS-SDPYVVLTLGNQKVKTRVIKKNLNPVWNEELTLSVPNP-MAPLKLEVFDKDTFSKDDS 78

                          90
                  ....*....|....*.
gi 688602146 1590 LGRTEV---PVATIKK 1602
Cdd:cd04038    79 MGEAEIdlePLVEAAK 94

Third Src Homology 3 domain of Nck adaptor proteins; This group contains the third SH3 domain of Nck, the first SH3 domain of Caenorhabditis elegans Ced-2 (Cell death abnormality protein 2), and similar domains. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The third SH3 domain of Nck appears to prefer ligands with a PxAPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. Ced-2 is a cell corpse engulfment protein that interacts with Ced-5 in a pathway that regulates the activation of Ced-10, a Rac small GTPase.

Pssm-ID: 212701 [Multi-domain] Cd Length: 56 Bit Score: 58.86 E-value: 6.98e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNK--DNPDWWKGEVA-GVTGLFPTNYVK 1126
Cdd:cd11767     2 VVALYPFTGENDEELSFEKGERLEIIEKpeDDPDWWKARNAlGTTGLVPRNYVE 55

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212909 [Multi-domain] Cd Length: 54 Bit Score: 58.80 E-value: 8.63e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPD-WWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11976     4 ARYDFCARDRSELSLKEGDIIKILNKKGQQgWWRGEIYGRVGWFPANYVE 53

Src Homology 3 domain of beta-Pak Interactive eXchange factor; Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212994 [Multi-domain] Cd Length: 54 Bit Score: 58.54 E-value: 8.80e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12061     2 VRAKFNFQQTNEDELSFSKGDVIHVTRVEEGGWWEGTHNGRTGWFPSNYVR 52

Third Src Homology 3 domain (SH3C) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CD2AP. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212989 [Multi-domain] Cd Length: 57 Bit Score: 58.30 E-value: 1.32e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKD--NPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd12056     6 ALFHYEGTNEDELDFKEGEIILIISKDtgEPGWWKGELNGKEGVFPDNFV 55

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

Pssm-ID: 212690 [Multi-domain] Cd Length: 51 Bit Score: 57.86 E-value: 1.52e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNR-GWFPESY 802
Cdd:cd00174     1 YARALYDYEAQDDDELSFKKGDIITVLEKD--DDGWWEGELNGGReGLFPANY 51

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

Pssm-ID: 214620 [Multi-domain] Cd Length: 56 Bit Score: 57.93 E-value: 1.53e-10

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146    751 TYRALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSY-SGNRGWFPESYAE 804
Cdd:smart00326    4 QVRALYDYTAQDPDELSFKKGDIITVLEKS--DDGWWKGRLgRGKEGLFPSNYVE 56

Second Src Homology 3 domain (SH3B) of CD2-associated protein and similar proteins; This subfamily is composed of the second SH3 domain (SH3B) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3B of both proteins have been shown to bind to Cbl. In the case of CD2AP, its SH3B binds to Cbl at a site distinct from the c-Cbl/SH3A binding site. The CIN85 SH3B also binds ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212807 [Multi-domain] Cd Length: 53 Bit Score: 57.73 E-value: 1.71e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1074 CQVIamYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11874     2 CKVL--FSYTPQNEDELELKVGDTIEVLGEVEEGWWEGKLNGKVGVFPSNFVKE 53

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 429575 [Multi-domain] Cd Length: 54 Bit Score: 57.61 E-value: 1.71e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 688602146   855 AVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHVSVV 906
Cdd:pfam07653    2 GRVIFDYVGTDKNGLTLKKGDVVKVLGKdNDGWWEGETGGRVGLVPSTAVEEI 54

Fifth Src homology 3 domain (or SH3E) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212774 [Multi-domain] Cd Length: 53 Bit Score: 57.81 E-value: 1.83e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11840     1 QVIALFPYTAQNEDELSFQKGDIINVLSKDDpDWWRGELNGQTGLFPSNYVEP 53

Src Homology 3 domain of Mixed Lineage Kinases 1, 2, and 3; MLKs 1, 2, and 3 are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Little is known about the specific function of MLK1, also called MAP3K9. It is capable of activating the c-Jun N-terminal kinase pathway. Mice lacking both MLK1 and MLK2 are viable, fertile, and have normal life spans. MLK2, also called MAP3K10, is abundant in brain, skeletal muscle, and testis. It functions upstream of the MAPK, c-Jun N-terminal kinase. It binds hippocalcin, a calcium-sensor protein that protects neurons against calcium-induced cell death. Both MLK2 and hippocalcin may be associated with the pathogenesis of Parkinson's disease. MLK3, also called MAP3K11, is highly expressed in breast cancer cells and its signaling through c-Jun N-terminal kinase has been implicated in the migration, invasion, and malignancy of cancer cells. It also functions as a negative regulator of Inhibitor of Nuclear Factor-KappaB Kinase (IKK) and thus, impacts inflammation and immunity. MLKs contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212992 [Multi-domain] Cd Length: 58 Bit Score: 57.85 E-value: 1.91e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKD-----NPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd12059     4 AVFDYEASAEDELTLRRGDRVEVLSKDsavsgDEGWWTGKINDRVGIFPSNYVTS 58

Second Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212696 [Multi-domain] Cd Length: 57 Bit Score: 57.79 E-value: 2.08e-10

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPD----WWKGEVAGVTGLFPT 1122
Cdd:cd11762     4 ALYDYEAQSDEELSFPEGAIIRILRKDDNGvddgWWEGEFNGRVGVFPS 52

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar proteins; This subfamily is composed of Rho GTPase activating proteins (GAPs) with similarity to GRAF. Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. Although vertebrates harbor four Rho GAPs in the GRAF subfamily including GRAF, GRAF2, GRAF3, and Oligophrenin-1 (OPHN1), only three are included in this model. OPHN1 contains the BAR, PH and GAP domains, but not the C-terminal SH3 domain. GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. GRAF influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase. GRAF2 regulates caspase-activated p21-activated protein kinase-2. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212815 [Multi-domain] Cd Length: 54 Bit Score: 57.30 E-value: 2.32e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLIT-VLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11882     1 RARALYACKAEDESELSFEPGQIITnVQPSDEPGWLEGTLNGRTGLIPENYVE 53

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If (MyoIf) are nonmuscle, unconventional, long tailed, class I myosins containing an N-terminal motor domain and a myosin tail with TH1, TH2, and SH3 domains. MyoIe interacts with the endocytic proteins, dynamin and synaptojanin-1, through its SH3 domain; it may play a role in clathrin-dependent endocytosis. In the kidney, MyoIe is critical for podocyte function and normal glomerular filtration. Mutations in MyoIe is associated with focal segmental glomerulosclerosis, a disease characterized by massive proteinuria and progression to end-stage kidney disease. MyoIf is predominantly expressed in the immune system; it plays a role in immune cell motility and innate immunity. Mutations in MyoIf may be associated with the loss of hearing. The MyoIf gene has also been found to be fused to the MLL (Mixed lineage leukemia) gene in infant acute myeloid leukemias (AML). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212761 [Multi-domain] Cd Length: 53 Bit Score: 57.42 E-value: 2.44e-10

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  936 ALYTYESPESGDLTFSAEDVV-LVTEKEGEWWRGCIGDQTGLFPSNYV 982
Cdd:cd11827     4 ALYAYDAQDTDELSFNEGDIIeILKEDPSGWWTGRLRGKEGLFPGNYV 51

Src homology 3 domain of Fyn and Yrk Protein Tyrosine Kinases; Fyn and Yrk (Yes-related kinase) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Fyn, together with Lck, plays a critical role in T-cell signal transduction by phosphorylating ITAM (immunoreceptor tyr activation motif) sequences on T-cell receptors, ultimately leading to the proliferation and differentiation of T-cells. In addition, Fyn is involved in the myelination of neurons, and is implicated in Alzheimer's and Parkinson's diseases. Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212939 [Multi-domain] Cd Length: 56 Bit Score: 57.37 E-value: 2.58e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGE--VAGVTGLFPTNYV 1125
Cdd:cd12006     4 VALYDYEARTEDDLSFHKGEKFQILNSSEGDWWEARslTTGETGYIPSNYV 54

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing (Stac) proteins; Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. This model represents the first C-terminal SH3 domain of Stac1 and Stac3, and the single C-terminal SH3 domain of Stac2. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212767 [Multi-domain] Cd Length: 53 Bit Score: 57.13 E-value: 2.68e-10

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11833     3 VALYKFKPQENEDLEMRPGDKITLLDDSNEDWWKGKIEDRVGFFPANFV 51

Src homology 3 domain of Phospholipase C (PLC) gamma 1; PLCgamma1 is widely expressed and is essential in growth and development. It is activated by the TrkA receptor tyrosine kinase and functions as a key regulator of cell differentiation. It is also the predominant PLCgamma in T cells and is required for T cell and NK cell function. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212903 Cd Length: 60 Bit Score: 57.31 E-value: 3.05e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1074 CQVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGL-FPTNYVK 1126
Cdd:cd11970     4 CAVKALFDYKAQREDELTFTKNAIIQNVEKQEGGWWRGDYGGKKQLwFPSNYVE 57

Second Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis. Together with other proteins, it induces membrane scission in yeast. Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This model represents the second C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212712 [Multi-domain] Cd Length: 51 Bit Score: 57.12 E-value: 3.11e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPD-WWKGEVAGVTGLFPTNY 1124
Cdd:cd11778     2 VEALYDYEAQGDDEISIRVGDRIAVIRGDDGSgWTYGEINGVKGLFPTSY 51

Src Homology 3 domain of Sdc25/Cdc25 guanine nucleotide exchange factors; This subfamily is composed of the Saccharomyces cerevisiae guanine nucleotide exchange factors (GEFs) Sdc25 and Cdc25, and similar proteins. These GEFs regulate Ras by stimulating the GDP/GTP exchange on Ras. Cdc25 is involved in the Ras/PKA pathway that plays an important role in the regulation of metabolism, stress responses, and proliferation, depending on available nutrients and conditions. Proteins in this subfamily contain an N-terminal SH3 domain as well as REM (Ras exchanger motif) and RasGEF domains at the C-terminus. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212816 Cd Length: 55 Bit Score: 56.91 E-value: 4.16e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAG-----VTGLFPTNY 1124
Cdd:cd11883     2 VVALYDFTPKSKNQLSFKAGDIIYVLNKDPSGWWDGVIISssgkvKRGWFPSNY 55

C-terminal Src Homology 3 domain of the Nebulin family of proteins; Nebulin family proteins contain multiple nebulin repeats, and may contain an N-terminal LIM domain and/or a C-terminal SH3 domain. They have molecular weights ranging from 34 to 900 kD, depending on the number of nebulin repeats, and they all bind actin. They are involved in the regulation of actin filament architecture and function as stabilizers and scaffolds for cytoskeletal structures with which they associate, such as long actin filaments or focal adhesions. Nebulin family proteins that contain a C-terminal SH3 domain include the giant filamentous protein nebulin, nebulette, Lasp1, and Lasp2. Lasp2, also called LIM-nebulette, is an alternatively spliced variant of nebulette. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212723 [Multi-domain] Cd Length: 55 Bit Score: 56.56 E-value: 5.08e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVA--GVTGLFPTNYVKM 1127
Cdd:cd11789     1 RYRAMYDYAAADDDEVSFQEGDVIINVEIIDDGWMEGTVQrtGQSGMLPANYVEL 55

Src homology 3 domain of eumetazoan Actin-binding protein 1; Abp1, also called drebrin-like protein, is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a helical domain, and a C-terminal SH3 domain. Mammalian Abp1, unlike yeast Abp1, does not contain an acidic domain that interacts with the Arp2/3 complex. It regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. Abp1 deficiency causes abnormal organ structure and function of the spleen, heart, and lung of mice. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212893 [Multi-domain] Cd Length: 54 Bit Score: 56.25 E-value: 5.47e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEV-AGVTGLFPTNYVKM 1127
Cdd:cd11960     2 ARALYDYQAADDTEISFDPGDIITDIEQIDEGWWRGTGpDGTYGLFPANYVEL 54

Third Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212750 [Multi-domain] Cd Length: 51 Bit Score: 56.26 E-value: 5.89e-10

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11816     3 VARFDFEGEQEDELSFSEGDVITLKEYVGEEWAKGELNGKIGIFPLNFV 51

C2 domain found in Rab11-family interacting proteins (FIP) class I; Rab GTPases recruit various effector proteins to organelles and vesicles. Rab11-family interacting proteins (FIPs) are involved in mediating the role of Rab11. FIPs can be divided into three classes: class I FIPs (Rip11a, Rip11b, RCP, and FIP2) which contain a C2 domain after N-terminus of the protein, class II FIPs (FIP3 and FIP4) which contain two EF-hands and a proline rich region, and class III FIPs (FIP1) which exhibits no homology to known protein domains. All FIP proteins contain a highly conserved, 20-amino acid motif at the C-terminus of the protein, known as Rab11/25 binding domain (RBD). Class I FIPs are thought to bind to endocytic membranes via their C2 domain, which interacts directly with phospholipids. Class II FIPs do not have any membrane binding domains leaving much to speculate about the mechanism involving FIP3 and FIP4 interactions with endocytic membranes. The members in this CD are class I FIPs. The exact function of the Rab11 and FIP interaction is unknown, but there is speculation that it involves the role of forming a targeting complex that recruits a group of proteins involved in membrane transport to organelles. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 176064 [Multi-domain] Cd Length: 126 Bit Score: 58.62 E-value: 7.14e-10

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1515 VTVLEATELKPCKPNGKSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLY-----QDVLCLTVFERDQFSPDDF 1589
Cdd:cd08682     3 VTVLQARGLLCKGKSGTNDAYVIIQLGKEKYSTSVKEKTTSPVWKEECSFELPGLLsgngnRATLQLTVMHRNLLGLDKF 82

                          90
                  ....*....|....*.
gi 688602146 1590 LGRTEVPVATIKKDQD 1605
Cdd:cd08682    83 LGQVSIPLNDLDEDKG 98

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar proteins; This subfamily is composed of Rho GTPase activating proteins (GAPs) with similarity to GRAF. Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. Although vertebrates harbor four Rho GAPs in the GRAF subfamily including GRAF, GRAF2, GRAF3, and Oligophrenin-1 (OPHN1), only three are included in this model. OPHN1 contains the BAR, PH and GAP domains, but not the C-terminal SH3 domain. GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. GRAF influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase. GRAF2 regulates caspase-activated p21-activated protein kinase-2. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212815 [Multi-domain] Cd Length: 54 Bit Score: 55.76 E-value: 8.54e-10

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                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  753 RALYPFTARNSDELTLEA-DCFIQVDEStvRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11882     3 RALYACKAEDESELSFEPgQIITNVQPS--DEPGWLEGTLNGRTGLIPENYVE 53

Variant SH3 domain;

Pssm-ID: 434066 [Multi-domain] Cd Length: 49 Bit Score: 55.70 E-value: 8.58e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 688602146   754 ALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNRGWFPESYAE 804
Cdd:pfam14604    1 ALYPYEPKDDDELSLQRGDVITVIEES--EDGWWEGINTGRTGLVPANYVE 49

Src Homology 3 domain of Tec-like Protein Tyrosine Kinases; The Tec (Tyrosine kinase expressed in hepatocellular carcinoma) subfamily is composed of Tec, Btk, Bmx (Etk), Itk (Tsk, Emt), Rlk (Txk), and similar proteins. They are cytoplasmic (or nonreceptor) tyr kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Most Tec subfamily members (except Rlk) also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, some members contain the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. Tec kinases are expressed mainly by haematopoietic cells, although Tec and Bmx are also found in endothelial cells. B-cells express Btk and Tec, while T-cells express Itk, Txk, and Tec. Collectively, Tec kinases are expressed in a variety of myeloid cells such as mast cells, platelets, macrophages, and dendritic cells. Each Tec kinase shows a distinct cell-type pattern of expression. The function of Tec kinases in lymphoid cells have been studied extensively. They play important roles in the development, differentiation, maturation, regulation, survival, and function of B-cells and T-cells. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212702 [Multi-domain] Cd Length: 54 Bit Score: 55.74 E-value: 8.74e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWK-----GEVagvtGLFPTNYVK 1126
Cdd:cd11768     1 IVVALYDFQPIEPGDLPLEKGEEYVVLDDSNEHWWRardknGNE----GYIPSNYVT 53

Src homology 3 domain of Apoptosis Stimulating of p53 proteins (ASPP); The ASPP family of proteins bind to important regulators of apoptosis (p53, Bcl-2, and RelA) and cell growth (APCL, PP1). They share similarity at their C-termini, where they harbor a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain. Vertebrates contain three members of the family: ASPP1, ASPP2, and iASPP. ASPP1 and ASPP2 activate the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73), while iASPP is an oncoprotein that specifically inhibits p53-induced apoptosis. The expression of ASPP proteins is altered in tumors; ASPP1 and ASPP2 are downregulated whereas iASPP is upregulated is some cancer types. ASPP proteins also bind and regulate protein phosphatase 1 (PP1), and this binding is competitive with p53 binding. The SH3 domain and the ANK repeats of ASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212741 [Multi-domain] Cd Length: 57 Bit Score: 55.85 E-value: 8.78e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPD---WWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11807     2 VVYALFDYEAENGDELSFREGDELTVLRKGDDDeteWWWARLNDKEGYVPRNLLGL 57

Src Homology 3 domain of alpha-Pak Interactive eXchange factor; Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6) or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212993 Cd Length: 58 Bit Score: 55.78 E-value: 8.98e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12060     4 VKARFNFKQTNEDELSVCKGDIIYVTRVEEGGWWEGTLNGKTGWFPSNYVR 54

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 394975 [Multi-domain] Cd Length: 47 Bit Score: 55.67 E-value: 9.27e-10

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 688602146   935 VALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRG-CIGDQTGLFPS 979
Cdd:pfam00018    1 VALYDYTAQEPDELSFKKGDIIIVLEKsEDGWWKGrNKGGKEGLIPS 47

First Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the first SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212715 [Multi-domain] Cd Length: 53 Bit Score: 55.42 E-value: 1.13e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11781     3 RALYPFKAQSAKELSLKKGDIIYIRRQIDKNWYEGEHNGRVGIFPASYVEI 53

Third Src homology 3 domain (or SH3C) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (SH3C) of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212925 Cd Length: 52 Bit Score: 55.40 E-value: 1.15e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNpDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11992     1 EYIALYPYSSSEPGDLTFNEGEEILVTQKDG-EWWTGSIEDRTGIFPSNYVR 51

Src homology 3 domain of Ubiquitin-associated and SH3 domain-containing proteins, also called TULA (T cell Ubiquitin LigAnd) family of proteins; UBASH3 or TULA proteins are also referred to as Suppressor of T cell receptor Signaling (STS) proteins. They contain an N-terminal UBA domain, a central SH3 domain, and a C-terminal histidine phosphatase domain. They bind c-Cbl through the SH3 domain and to ubiquitin via UBA. In some vertebrates, there are two TULA family proteins, called UBASH3A (also called TULA or STS-2) and UBASH3B (also called TULA-2 or STS-1), which show partly overlapping as well as distinct functions. UBASH3B is widely expressed while UBASH3A is only found in lymphoid cells. UBASH3A facilitates apoptosis induced in T cells through its interaction with the apoptosis-inducing factor AIF. UBASH3B is an active phosphatase while UBASH3A is not. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212725 [Multi-domain] Cd Length: 59 Bit Score: 55.38 E-value: 1.25e-09

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDESTVRET--GWLYGsYS---GNRGWFPESYAER 805
Cdd:cd11791     1 VLRVLYPYTPQEEDELELVPGDYIYVSPEELDSSsdGWVEG-TSwltGCSGLLPENYTEK 59

Fifth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212752 [Multi-domain] Cd Length: 50 Bit Score: 55.18 E-value: 1.37e-09

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNY 1124
Cdd:cd11818     4 ALYDFTGENEDELSFKAGDIITELESIDEEWMSGELRGKSGIFPKNF 50

C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing protein 2 (Stac2); Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac2 contains a single SH3 domain at the C-terminus unlike Stac1 and Stac3, which contain two C-terminal SH3 domains. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212918 Cd Length: 53 Bit Score: 55.34 E-value: 1.40e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11985     2 YVALYKFLPQENNDLPLQPGDRVMVVDDSNEdWWKGKSGDRVGFFPANFVQ 52

Src homology 3 domain of Abl Interactor proteins; Abl interactor (Abi) proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. They localize to sites of actin polymerization in epithelial adherens junction and immune synapses, as well as to the leading edge of lamellipodia. Vertebrates contain two Abi proteins, Abi1 and Abi2. Abi1 displays a wide expression pattern while Abi2 is highly expressed in the eye and brain. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212760 [Multi-domain] Cd Length: 52 Bit Score: 55.02 E-value: 1.53e-09

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYV 982
Cdd:cd11826     3 VALYDYTADKDDELSFQEGDIIYVTKKNDDgWYEGVLNGVTGLFPGNYV 51

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212810 [Multi-domain] Cd Length: 53 Bit Score: 55.01 E-value: 1.55e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVdeSTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11877     1 LVRAKFNFEGTNEDELSFDKGDIITV--TQVVEGGWWEGTLNGKTGWFPSNYVK 52

Src homology 3 domain of ARHGEF9-like Rho guanine nucleotide exchange factors; Members of this family contain a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. They include the Rho guanine nucleotide exchange factors ARHGEF9, ASEF (also called ARHGEF4), ASEF2, and similar proteins. GEFs activate small GTPases by exchanging bound GDP for free GTP. ARHGEF9 specifically activates Cdc42, while both ASEF and ASEF2 can activate Rac1 and Cdc42. ARHGEF9 is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. ASEF plays a role in angiogenesis and cell migration. ASEF2 is important in cell migration and adhesion dynamics. ASEF exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli), leading to the activation of Rac1 or Cdc42. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212762 [Multi-domain] Cd Length: 53 Bit Score: 55.08 E-value: 1.76e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11828     2 AEALWDHVTMDPEELGFKAGDVIEVLDMSDKDWWWGSIRDEEGWFPASFVRL 53

Src homology 3 domain of Cortactin and related proteins; This subfamily includes cortactin, Abp1 (actin-binding protein 1), hematopoietic lineage cell-specific protein 1 (HS1), and similar proteins. These proteins are involved in regulating actin dynamics through direct or indirect interaction with the Arp2/3 complex, which is required to initiate actin polymerization. They all contain at least one C-terminal SH3 domain. Cortactin and HS1 bind Arp2/3 and actin through an N-terminal region that contains an acidic domain and several copies of a repeat domain found in cortactin and HS1. Abp1 binds actin via an N-terminal actin-depolymerizing factor (ADF) homology domain. Yeast Abp1 binds Arp2/3 directly through two acidic domains. Mammalian Abp1 does not directly interact with Arp2/3; instead, it regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. The C-terminal region of these proteins acts as an adaptor or scaffold that can connect membrane trafficking and signaling proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212753 [Multi-domain] Cd Length: 54 Bit Score: 55.01 E-value: 1.86e-09

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEK--EGeWWRG-CIGDQTGLFPSNYVK 983
Cdd:cd11819     3 KALYDYQAAEDNEISFVEGDIITQIEQidEG-WWLGvNAKGQKGLFPANYVE 53

Second Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the second SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212716 [Multi-domain] Cd Length: 53 Bit Score: 54.66 E-value: 1.93e-09

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11782     1 EARAKYNFNADTGVELSFRKGDVITLTRRVDENWYEGRIGGRQGIFPVSYVQ 52

Src Homology 3 domain of C-terminal Src kinase; CSK is a cytoplasmic (or nonreceptor) tyr kinase containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. They negatively regulate the activity of Src kinases that are anchored to the plasma membrane. To inhibit Src kinases, CSK is translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. CSK catalyzes the tyr phosphorylation of the regulatory C-terminal tail of Src kinases, resulting in their inactivation. It is expressed in a wide variety of tissues and plays a role, as a regulator of Src, in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. In addition, CSK also shows Src-independent functions. It is a critical component in G-protein signaling, and plays a role in cytoskeletal reorganization and cell migration. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212703 [Multi-domain] Cd Length: 57 Bit Score: 54.62 E-value: 2.56e-09

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                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLN--KDnPDWWKGE-VAGVTGLFPTNYVK 1126
Cdd:cd11769     3 ECIAKYNFNGASEEDLPFKKGDILTIVAvtKD-PNWYKAKnKDGREGMIPANYVQ 56

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing (Stac) proteins; Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. This model represents the first C-terminal SH3 domain of Stac1 and Stac3, and the single C-terminal SH3 domain of Stac2. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212767 [Multi-domain] Cd Length: 53 Bit Score: 54.43 E-value: 3.00e-09

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                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYV 982
Cdd:cd11833     2 YVALYKFKPQENEDLEMRPGDKITLLDDSNEdWWKGKIEDRVGFFPANFV 51

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212790 [Multi-domain] Cd Length: 53 Bit Score: 54.18 E-value: 3.24e-09

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                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11856     1 SYVAIADYEAQGDDEISLQEGEVVEVLEKnDSGWWYVRKGDKEGWVPASYLEP 53

Fourth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212751 [Multi-domain] Cd Length: 50 Bit Score: 54.02 E-value: 3.25e-09

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                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNY 1124
Cdd:cd11817     2 AVALYDFTGETEEDLSFQRGDRILVTEHLDAEWSRGRLNGREGIFPRAF 50

Src homology 3 domain of Yes Protein Tyrosine Kinase; Yes (or c-Yes) is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. c-Yes kinase is the cellular homolog of the oncogenic protein (v-Yes) encoded by the Yamaguchi 73 and Esh sarcoma viruses. It displays functional overlap with other Src subfamily members, particularly Src. It also shows some unique functions such as binding to occludins, transmembrane proteins that regulate extracellular interactions in tight junctions. Yes also associates with a number of proteins in different cell types that Src does not interact with, like JAK2 and gp130 in pre-adipocytes, and Pyk2 in treated pulmonary vein endothelial cells. Although the biological function of Yes remains unclear, it appears to have a role in regulating cell-cell interactions and vesicle trafficking in polarized cells. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212940 [Multi-domain] Cd Length: 58 Bit Score: 54.27 E-value: 3.53e-09

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                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGE--VAGVTGLFPTNYV 1125
Cdd:cd12007     4 VALYDYEARTTEDLSFKKGERFQIINNTEGDWWEARsiATGKNGYIPSNYV 54

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212810 [Multi-domain] Cd Length: 53 Bit Score: 53.86 E-value: 3.77e-09

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                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11877     4 AKFNFEGTNEDELSFDKGDIITVTQVvEGGWWEGTLNGKTGWFPSNYVKE 53

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The C-terminal SH3 domains (SH3c) of GRB2 and GRAP2 have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212739 [Multi-domain] Cd Length: 53 Bit Score: 53.79 E-value: 4.33e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11805     1 RVQALYDFNPQEPGELEFRRGDIITVLDSsDPDWWKGELRGRVGIFPANYVQP 53

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing protein 3 (Stac3); Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212919 [Multi-domain] Cd Length: 53 Bit Score: 53.76 E-value: 5.10e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  934 YVALYTYESPESGDLTFSA-EDVVLVTEKEGEWWRGCIGDQTGLFPSNYV 982
Cdd:cd11986     2 FVALYRFKALEKDDLDFHPgERITVIDDSNEEWWRGKIGEKTGYFPMNFI 51

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and scaffold proteins and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212764 [Multi-domain] Cd Length: 54 Bit Score: 53.79 E-value: 5.13e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPD-WWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11830     3 KARYDFCARDMRELSLKEGDVVKIYNKKGQQgWWRGEINGRIGWFPSTYVE 53

First Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212853 [Multi-domain] Cd Length: 55 Bit Score: 53.48 E-value: 5.79e-09

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11920     5 AVYDFKAQTSKELSFKKGDTVYILRKIDQNWYEGEHHGRVGIFPISYVE 53

Third Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The third SH3 domain of Nck appears to prefer ligands with a PxAPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212837 [Multi-domain] Cd Length: 57 Bit Score: 53.49 E-value: 6.02e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNK--DNPDWWK-GEVAGVTGLFPTNYV 1125
Cdd:cd11904     3 VQALYPFSSSNDEELNFEKGEVMDVIEKpeNDPEWWKcRKANGQVGLVPKNYV 55

First Src Homology 3 domain of SH3 domain containing ring finger proteins; This model represents the first SH3 domain of SH3RF1 (or POSH), SH3RF2 (or POSHER), SH3RF3 (POSH2), and similar domains. Members of this family are scaffold proteins that function as E3 ubiquitin-protein ligases. They all contain an N-terminal RING finger domain and multiple SH3 domains; SH3RF1 and SH3RF3 have four SH3 domains while SH3RF2 has three. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3RF2 acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212720 [Multi-domain] Cd Length: 53 Bit Score: 53.52 E-value: 6.26e-09

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11786     4 ALYNYEGKEPGDLSFKKGDIILLRKRIDENWYHGECNGKQGFFPASYVQ 52

Src Homology 3 (SH3) domain of Inhibitor of ASPP protein (iASPP); iASPP, also called RelA-associated inhibitor (RAI), is an oncoprotein that inhibits the apoptotic transactivation potential of p53. It is upregulated in human breast cancers expressing wild-type p53, in acute leukemias regardless of the p53 mutation status, as well as in ovarian cancer where it is associated with poor patient outcome and chemoresistance. iASPP is also a binding partner and negative regulator of p65RelA, which promotes cell proliferation and inhibits apoptosis; p65RelA has the opposite effect on cell growth compared to the p53 family. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of iASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212885 [Multi-domain] Cd Length: 56 Bit Score: 53.39 E-value: 7.73e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNP--DWWKGEVAGVTGLFPTNY 1124
Cdd:cd11952     3 VYALWDYSAEFPDELSFKEGDMVTVLRKDGEgtDWWWASLCGREGYVPRNY 53

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212754 [Multi-domain] Cd Length: 54 Bit Score: 53.24 E-value: 8.25e-09

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11820     5 ALYDFEAAEDNELTFKAGEIITVLDDSDPnWWKGSNHRGEGLFPANFVT 53

Second Src Homology 3 domain of FCH and double SH3 domains protein 2; FCHSD2 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212827 Cd Length: 56 Bit Score: 53.02 E-value: 8.30e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPD---WWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11894     2 VKALYDYEGQTDDELSFPEGAIIRILNKENQDddgFWEGEFNGRIGVFPSVLVE 55

Second Src homology 3 domain (or SH3B) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212771 [Multi-domain] Cd Length: 53 Bit Score: 53.14 E-value: 8.45e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGEWWRG-CIGDQTGLFPSNYVKP 984
Cdd:cd11837     2 ATALYPWRAKKENHLSFAKGDIITVLEQQEMWWFGeLEGGEEGWFPKSYVKE 53

Fourth Src homology 3 domain (or SH3D) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212773 [Multi-domain] Cd Length: 58 Bit Score: 53.11 E-value: 8.98e-09

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1073 LCQVIAmyDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAG-----VTGLFPTNYVKM 1127
Cdd:cd11839     1 IAQVIA--PFTATAENQLSLAVGQLVLVRKKSPSGWWEGELQArgkkrQIGWFPANYVKL 58

Septal ring factor EnvC, activator of murein hydrolases AmiA and AmiB [Cell cycle control, cell division, chromosome partitioning];

Pssm-ID: 443969 [Multi-domain] Cd Length: 377 Bit Score: 59.39 E-value: 9.03e-09

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  452 SKRVELQTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRQGQWAELELINQRrdvcitdINSLQLQF 531
Cdd:COG4942    20 DAAAEAEAELEQLQQEIAELEKELAALKKEEKALLKQLAALERRIAALARRIRALEQELAALEAE-------LAELEKEI 92

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  532 DEMQRQLNQLgpeKQRLADRLVHFTQNISSP-----------------------LINDVKQSVCEKDRSCRKLKEQLDVL 588
Cdd:COG4942    93 AELRAELEAQ---KEELAELLRALYRLGRQPplalllspedfldavrrlqylkyLAPARREQAEELRADLAELAALRAEL 169

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  589 ERETTAKLSQMEQYNKEIKELRQKQSQQQDVLEQLRRVRSDKLKELQR 636
Cdd:COG4942   170 EAERAELEALLAELEEERAALEALKAERQKLLARLEKELAELAAELAE 217

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. Also included in this subfamily is the second C-terminal SH3 domain of Rho guanine nucleotide exchange factor 37 (ARHGEF37), whose function is still unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212734 [Multi-domain] Cd Length: 57 Bit Score: 53.14 E-value: 9.52e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLN----KDNPDWWKGEVAGVTGLFPTNY 1124
Cdd:cd11800     1 YYYALYTFEARSPGELSVTEGQVVTVLEkhdlKGNPEWWLVEDRGKQGYVPSNY 54

RIM-binding protein of the cytomatrix active zone; This is a family of proteins that form part of the CAZ (cytomatrix at the active zone) complex which is involved in determining the site of synaptic vesicle fusion. The C-terminus is a PDZ-binding motif that binds directly to RIM (a small G protein Rab-3A effector). The family also contains four coiled-coil domains.

Pssm-ID: 431111 [Multi-domain] Cd Length: 766 Bit Score: 60.22 E-value: 9.79e-09

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   459 TQKEKEQNDIQRLKDRKRSLEIELEAVGNKHkqiSSQLRDAKSKRQGQWAELELINQRRDVCITDINSLQLQFDEMQRQL 538
Cdd:pfam10174  334 TAKEQRAAILQTEVDALRLRLEEKESFLNKK---TKQLQDLTEEKSTLAGEIRDLKDMLDVKERKINVLQKKIENLQEQL 410

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   539 ----NQLGPEKQRLADrLVHFTQNISSPLINdVKQSVCEKDRSCRKLKEQLDVLEREttaKLSQMEQYNKEIKELRQKQS 614
Cdd:pfam10174  411 rdkdKQLAGLKERVKS-LQTDSSNTDTALTT-LEEALSEKERIIERLKEQREREDRE---RLEELESLKKENKDLKEKVS 485

                          170       180
                   ....*....|....*....|....
gi 688602146   615 -QQQDVLEqlrrvRSDKLKELQRH 637
Cdd:pfam10174  486 aLQPELTE-----KESSLIDLKEH 504

C-terminal Src Homology 3 domain of the p67phox subunit of NADPH oxidase and similar proteins; This subfamily is composed of p67phox, NADPH oxidase activator 1 (Noxa1), and similar proteins. p67phox, also called Neutrophil cytosol factor 2 (NCF-2), and Noxa1 are homologs and are the cytosolic subunits of the phagocytic (Nox2) and nonphagocytic (Nox1) NADPH oxidase complexes, respectively. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox and Noxa1 play regulatory roles. p67phox contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. Noxa1 has a similar domain architecture except it is lacking the N-terminal SH3 domain. The TPR domain of both binds activated GTP-bound Rac, while the C-terminal SH3 domain of p67phox and Noxa1 binds the polyproline motif found at the C-terminus of p47phox and Noxo1, respectively. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212803 [Multi-domain] Cd Length: 53 Bit Score: 52.92 E-value: 1.02e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11870     1 QVVALHRYEAQGPEDLGFREGDTIDVLSEVNEAWLEGHSDGRVGIFPKCFVV 52

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 394975 [Multi-domain] Cd Length: 47 Bit Score: 52.59 E-value: 1.03e-08

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 688602146   856 VALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKE-KRGWFPC 900
Cdd:pfam00018    1 VALYDYTAQEPDELSFKKGDIIIVLEKSEdGWWKGRNKGgKEGLIPS 47

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212882 [Multi-domain] Cd Length: 53 Bit Score: 52.53 E-value: 1.14e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVV-LVTEKEGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11949     4 ALFDFDPQEDGELGFRRGDFIeVMDNSDPNWWKGACHGQTGMFPRNYVTP 53

Src Homology 3 domain of Amphiphysin and related domains; Amphiphysins function primarily in endocytosis and other membrane remodeling events. They exist in several isoforms and mammals possess two amphiphysin proteins from distinct genes. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin, and synaptojanin. They function in synaptic vesicle endocytosis. Human autoantibodies to amphiphysin I hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy. Amphiphysins contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. The SH3 domain of amphiphysins bind proline-rich motifs present in binding partners such as dynamin, synaptojanin, and nsP3. It also belongs to a subset of SH3 domains that bind ubiquitin in a site that overlaps with the peptide binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212724 [Multi-domain] Cd Length: 64 Bit Score: 52.72 E-value: 1.33e-08

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 688602146  749 LTTYRALYPFTARNSDELTLEADCFIQV---DESTVRETGWLYG--SYSGNRGWFPESYAER 805
Cdd:cd11790     2 LYKVRATHDYTAEDTDELTFEKGDVILVipfDDPEEQDEGWLMGvkESTGCRGVFPENFTER 63

First C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212895 [Multi-domain] Cd Length: 54 Bit Score: 52.49 E-value: 1.52e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVA-GVTGLFPTNYVKM 1127
Cdd:cd11962     3 VVLYDYEKDEDNEIELVEGEIVTNIEMVDEDWWMGTNSkGESGLFPSNYVEL 54

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212757 [Multi-domain] Cd Length: 53 Bit Score: 52.34 E-value: 1.64e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDEStvRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11823     3 KALYSYTANREDELSLQPGDIIEVHEK--QDDGWWLGELNGKKGIFPATYVE 52

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212757 [Multi-domain] Cd Length: 53 Bit Score: 51.96 E-value: 1.88e-08

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYV 982
Cdd:cd11823     3 KALYSYTANREDELSLQPGDIIEVHEKQDDgWWLGELNGKKGIFPATYV 51

N-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also have roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The N-terminal SH3 domain of the related protein GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212880 [Multi-domain] Cd Length: 52 Bit Score: 52.10 E-value: 1.88e-08

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNpDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11947     4 GKFDFTASGEDELSFKKGDVLKILSSDD-IWFKAELNGEEGYVPKNFV 50

Src Homology 3 domain of Sdc25/Cdc25 guanine nucleotide exchange factors; This subfamily is composed of the Saccharomyces cerevisiae guanine nucleotide exchange factors (GEFs) Sdc25 and Cdc25, and similar proteins. These GEFs regulate Ras by stimulating the GDP/GTP exchange on Ras. Cdc25 is involved in the Ras/PKA pathway that plays an important role in the regulation of metabolism, stress responses, and proliferation, depending on available nutrients and conditions. Proteins in this subfamily contain an N-terminal SH3 domain as well as REM (Ras exchanger motif) and RasGEF domains at the C-terminus. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212816 Cd Length: 55 Bit Score: 51.90 E-value: 1.99e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLEKQEN-WWYGEL-----KEKRGWFPCSH 902
Cdd:cd11883     3 VALYDFTPKSKNQLSFKAGDIIYVLNKDPSgWWDGVIisssgKVKRGWFPSNY 55

C-terminal Src Homology 3 domain of LIM and SH3 domain protein 1; Lasp1 is a cytoplasmic protein that binds focal adhesion proteins and is involved in cell signaling, migration, and proliferation. It is overexpressed in several cancer cells including breast, ovarian, bladder, and liver. In cancer cells, it can be found in the nucleus; its degree of nuclear localization correlates with tumor size and poor prognosis. Lasp1 is a 36kD protein containing an N-terminal LIM domain, two nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212867 [Multi-domain] Cd Length: 59 Bit Score: 52.31 E-value: 2.00e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEV--AGVTGLFPTNYVK 1126
Cdd:cd11934     7 AVYDYNAADEDEVSFQDGDTIVNVQQIDDGWMYGTVerTGDTGMLPANYVE 57

Src homology 3 domain of Cortactin; Cortactin was originally identified as a substrate of Src kinase. It is an actin regulatory protein that binds to the Arp2/3 complex and stabilizes branched actin filaments. It is involved in cellular processes that affect cell motility, adhesion, migration, endocytosis, and invasion. It is expressed ubiquitously except in hematopoietic cells, where the homolog hematopoietic lineage cell-specific 1 (HS1) is expressed instead. Cortactin contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region interacts with the Arp2/3 complex and F-actin, and is crucial in regulating branched actin assembly. Cortactin also serves as a scaffold and provides a bridge to the actin cytoskeleton for membrane trafficking and signaling proteins that bind to its SH3 domain. Binding partners for the SH3 domain of cortactin include dynamin2, N-WASp, MIM, FGD1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212892 [Multi-domain] Cd Length: 53 Bit Score: 52.03 E-value: 2.07e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11959     3 VALYDYQAADDDEISFDPDDIITNIEMIDEgWWRGVCRGKYGLFPANYVE 52

Src Homology 3 domain of the p40phox subunit of NADPH oxidase; p40phox, also called Neutrophil cytosol factor 4 (NCF-4), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p40phox positively regulates NADPH oxidase in both phosphatidylinositol-3-phosphate (PI3P)-dependent and PI3P-independent manner. It contains an N-terminal PX domain, a central SH3 domain, and a C-terminal PB1 domain that interacts with p67phox. The SH3 domain of p40phox binds to canonical polyproline and noncanonical motifs at the C-terminus of p47phox. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212802 Cd Length: 54 Bit Score: 51.73 E-value: 2.13e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11869     4 ALFDFTGNSKLELNFKAGDVIFLLSRVNKDWLEGTVRGATGIFPLSFVKI 53

Src homology 3 domain of Signal Transducing Adaptor Molecule 1; STAM1 is part of the endosomal sorting complex required for transport (ESCRT-0) and is involved in sorting ubiquitinated cargo proteins from the endosome. It may also be involved in the regulation of IL2 and GM-CSF mediated signaling, and has been implicated in neural cell survival. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212897 [Multi-domain] Cd Length: 55 Bit Score: 51.87 E-value: 2.20e-08

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  936 ALYTYESPESGDLTFSAEDVV-LVTEKEGEWWRGCIGDQTGLFPSNYV 982
Cdd:cd11964     5 AIYDFEAAEDNELTFKAGDIItILDDSDPNWWKGETPQGTGLFPSNFV 52

Src homology 3 domain of Blk Protein Tyrosine Kinase; Blk is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. It is expressed specifically in B-cells and is involved in pre-BCR (B-cell receptor) signaling. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212942 [Multi-domain] Cd Length: 54 Bit Score: 51.74 E-value: 2.33e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNpDWW--KGEVAGVTGLFPTNYV 1125
Cdd:cd12009     2 VIAQYDFVPSNERDLQLKKGEKLQVLKSDG-EWWlaKSLTTGKEGYIPSNYV 52

C2 domain second repeat present in Synaptotagmin-like proteins 1-4; All Slp members basically share an N-terminal Slp homology domain (SHD) and C-terminal tandem C2 domains (named the C2A domain and the C2B domain) with the SHD and C2 domains being separated by a linker sequence of various length. Slp1/JFC1 and Slp2/exophilin 4 promote granule docking to the plasma membrane. Additionally, their C2A domains are both Ca2+ independent, unlike the case in Slp3 and Slp4/granuphilin in which their C2A domains are Ca2+ dependent. It is thought that SHD (except for the Slp4-SHD) functions as a specific Rab27A/B-binding domain. In addition to Slps, rabphilin, Noc2, and Munc13-4 also function as Rab27-binding proteins. It has been demonstrated that Slp3 and Slp4/granuphilin promote dense-core vesicle exocytosis. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 175987 [Multi-domain] Cd Length: 162 Bit Score: 55.02 E-value: 2.49e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1499 AYQARSQKNSGIGRLLVTVLEATELKPCKPNGKSNPYCeltmgaQCY----TSRH-------QPDTLNPKW----SFNcQ 1563
Cdd:cd04020    15 SEGALKSKKPSTGELHVWVKEAKNLPALKSGGTSDSFV------KCYllpdKSKKskqktpvVKKSVNPVWnhtfVYD-G 87

                          90       100
                  ....*....|....*....|....*...
gi 688602146 1564 FFIKDLYQDVLCLTVFERDQFSPDDFLG 1591
Cdd:cd04020    88 VSPEDLSQACLELTVWDHDKLSSNDFLG 115

Src Homology 3 domain of eumetazoan Peroxisomal biogenesis factor 13; PEX13 is a peroxin and is required for protein import into the peroxisomal matrix and membrane. It is an integral membrane protein that is essential for the localization of PEX14 and the import of proteins containing the peroxisome matrix targeting signals, PTS1 and PTS2. Mutations of the PEX13 gene in humans lead to a wide range of peroxisome biogenesis disorders (PBDs), the most severe of which is known as Zellweger syndrome (ZS), a severe multisystem disorder characterized by hypotonia, psychomotor retardation, and neuronal migration defects. PEX13 contains two transmembrane regions and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212798 Cd Length: 58 Bit Score: 51.86 E-value: 2.76e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKD----NPDWWKGEVAGVT-GLFPTNYVK 1126
Cdd:cd11864     3 RAEYDFVAESEDELSFRAGDKLRLAPKElqprVRGWLLATVDGQKiGLVPANYVK 57

C-terminal (or second) Src homology 3 domain of VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration. It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212911 [Multi-domain] Cd Length: 56 Bit Score: 51.56 E-value: 2.88e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPD-WWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11978     4 IARYDFCARDMRELSLLKGDVVKIYTKMSTNgWWRGEVNGRVGWFPSTYVE 54

Src Homology 3 domain of Bbc1 and similar domains; This subfamily is composed of Saccharomyces cerevisiae Bbc1p, also called Mti1p (Myosin tail region-interacting protein), and similar proteins. Bbc1p interacts with and regulates type I myosins in yeast, Myo3p and Myo5p, which are involved in actin cytoskeletal reorganization. It also binds and inhibits Las17, a WASp family protein that functions as an activator of the Arp2/3 complex. Bbc1p contains an N-terminal SH3 domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212820 [Multi-domain] Cd Length: 60 Bit Score: 51.57 E-value: 3.15e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEV---AGVT--GLFPTNYV 1125
Cdd:cd11887     4 VKALYPYESDHEDDLNFDVGQLITVTEEEDADWYFGEYvdsNGNTkeGIFPKNFV 58

Variant SH3 domain;

Pssm-ID: 434066 [Multi-domain] Cd Length: 49 Bit Score: 51.08 E-value: 3.24e-08

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 688602146   936 ALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVK 983
Cdd:pfam14604    1 ALYPYEPKDDDELSLQRGDVITVIEEsEDGWWEGINTGRTGLVPANYVE 49

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212810 [Multi-domain] Cd Length: 53 Bit Score: 51.16 E-value: 3.25e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQEN-WWYGELKEKRGWFPCSHV 903
Cdd:cd11877     1 LVRAKFNFEGTNEDELSFDKGDIITVTQVVEGgWWEGTLNGKTGWFPSNYV 51

C2 domain first repeat in Munc13 (mammalian uncoordinated)-like proteins; C2-like domains are thought to be involved in phospholipid binding in a Ca2+ independent manner in both Unc13 and Munc13. Caenorabditis elegans Unc13 has a central domain with sequence similarity to PKC, which includes C1 and C2-related domains. Unc13 binds phorbol esters and DAG with high affinity in a phospholipid manner. Mutations in Unc13 results in abnormal neuronal connections and impairment in cholinergic neurotransmission in the nematode. Munc13 is the mammalian homolog which are expressed in the brain. There are 3 isoforms (Munc13-1, -2, -3) and are thought to play a role in neurotransmitter release and are hypothesized to be high-affinity receptors for phorbol esters. Unc13 and Munc13 contain both C1 and C2 domains. There are two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. Munc13 interacts with syntaxin, synaptobrevin, and synaptotagmin suggesting a role for these as scaffolding proteins. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-II topology.

Pssm-ID: 176058 [Multi-domain] Cd Length: 153 Bit Score: 54.30 E-value: 3.29e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1497 EKAYQARSQKNSGIGRLLVTVLEATELKPCKPNGKSNPYCEL----------------------------TMGAQC-YTS 1547
Cdd:cd08676    14 EALLERVREAEPPIFVLKVTVIEAKGLLAKDVNGFSDPYCMLgivpasrernsekskkrkshrkkavlkdTVPAKSiKVT 93

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146 1548 RHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDqfspDDFLGRTEVPVATIKKD 1603
Cdd:cd08676    94 EVKPQTLNPVWNETFRFEVEDVSNDQLHLDIWDHD----DDFLGCVNIPLKDLPSC 145

Second Src Homology 3 domain (SH3B) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CD2AP. SH3B binds to c-Cbl in a site (TPSSRPLR is the core binding motif) distinct from the c-Cbl/SH3A binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212987 [Multi-domain] Cd Length: 55 Bit Score: 51.51 E-value: 3.31e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1074 CQViaMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12054     3 CKV--LFEYVPQNEDELELKVGDIIDINEEVEEGWWSGTLNGKSGLFPSNFVK 53

Third Src Homology 3 domain of SH3 domain containing ring finger 1 (SH3RF1), SH3RF3, and similar domains; SH3RF1 (or POSH) and SH3RF3 (or POSH2) are scaffold proteins that function as E3 ubiquitin-protein ligases. They contain an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle of SH3RF1 and SH3RF3, and similar domains. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212717 [Multi-domain] Cd Length: 55 Bit Score: 51.24 E-value: 3.34e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGE--VAGVTGLFPTNYVK 1126
Cdd:cd11783     2 YVALYPYKPQKPDELELRKGEMYTVTEKCQDGWFKGTslRTGQSGVFPGNYVQ 54

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212777 [Multi-domain] Cd Length: 53 Bit Score: 51.27 E-value: 3.50e-08

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE--WWRGCIGDQTGLFPSNYV 982
Cdd:cd11843     4 ALYDYEGQESDELSFKAGDILTKLEEEDEqgWCKGRLDGRVGLYPANYV 52

Second Src homology 3 domain of Tyrosine kinase substrate with four SH3 domains; Tks4, also called SH3 and PX domain-containing protein 2B (SH3PXD2B) or HOFI, is a Src substrate and scaffolding protein that plays an important role in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. It is required in the formation of functional podosomes, EGF-induced membrane ruffling, and lamellipodia generation. It plays an important role in cellular attachment and cell spreading. Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. It contains an N-terminal Phox homology (PX) domain and four SH3 domains. This model characterizes the second SH3 domain of Tks4. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213009 [Multi-domain] Cd Length: 54 Bit Score: 51.19 E-value: 3.54e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTVRetGWLYGSYSGNRGWFPESYAER 805
Cdd:cd12076     3 YTVIYPYTARDQDEINLEKGAVVEVIQKNLE--GWWKIRYQGKEGWAPASYLKK 54

C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing protein 2 (Stac2); Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac2 contains a single SH3 domain at the C-terminus unlike Stac1 and Stac3, which contain two C-terminal SH3 domains. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212918 Cd Length: 53 Bit Score: 51.10 E-value: 4.24e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11985     3 VALYKFLPQENNDLPLQPGDRVMVVDDSNEDWWKGKSGDRVGFFPANFVQ 52

First Src Homology 3 domain of SH3 domain containing ring finger proteins; This model represents the first SH3 domain of SH3RF1 (or POSH), SH3RF2 (or POSHER), SH3RF3 (POSH2), and similar domains. Members of this family are scaffold proteins that function as E3 ubiquitin-protein ligases. They all contain an N-terminal RING finger domain and multiple SH3 domains; SH3RF1 and SH3RF3 have four SH3 domains while SH3RF2 has three. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3RF2 acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212720 [Multi-domain] Cd Length: 53 Bit Score: 50.82 E-value: 4.27e-08

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11786     4 ALYNYEGKEPGDLSFKKGDIILLRKRIDEnWYHGECNGKQGFFPASYVQ 52

First Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212707 [Multi-domain] Cd Length: 57 Bit Score: 51.27 E-value: 4.31e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVT-------GLFPTNY 1124
Cdd:cd11773     4 ALYDYEPQTEDELTIQEDDILYLLEKSDDDWWKVKLKVNSsdddepvGLVPATY 57

C-terminal Src Homology 3 domain of Nebulin; Nebulin is a giant filamentous protein (600-900 kD) that is expressed abundantly in skeletal muscle. It binds to actin thin filaments and regulates its assembly and function. Nebulin was thought to be part of a molecular ruler complex that is critical in determining the lengths of actin thin filaments in skeletal muscle since its length, which varies due to alternative splicing, correlates with the length of thin filaments in various muscle types. Recent studies indicate that nebulin regulates thin filament length by stabilizing the filaments and preventing depolymerization. Mutations in nebulin can cause nemaline myopathy, characterized by muscle weakness which can be severe and can lead to neonatal lethality. Nebulin contains an N-terminal LIM domain, many nebulin repeats/super repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212866 [Multi-domain] Cd Length: 58 Bit Score: 51.16 E-value: 4.72e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEV--AGVTGLFPTNYVK 1126
Cdd:cd11933     6 AMYDYRAADDDEVSFKDGDTIVNVQTIDEGWMYGTVqrTGKTGMLPANYVE 56

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the peroxisomal membrane, contains two transmembrane regions and a C-terminal SH3 domain. It binds to the peroxisomal targeting type I (PTS1) receptor Pex5p and the docking factor Pex14p through its SH3 domain. It is essential for both PTS1 and PTS2 protein import pathways into the peroxisomal matrix. Pex13p binds Pex14p, which contains a PxxP motif, in a classical fashion to the proline-rich ligand binding site of its SH3 domain. It binds the WxxxF/Y motif of Pex5p in a novel site that does not compete with Pex14p binding. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212705 [Multi-domain] Cd Length: 60 Bit Score: 50.74 E-value: 5.54e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1078 AMYDYKAAN-KDEMSFQKGQLITVLNKDNP-----DWWKGEV-AGVTGLFPTNYV 1125
Cdd:cd11771     4 ALYDFTPENpEMELSLKKGDIVAVLSKTDPlgrdsEWWKGRTrDGRIGWFPSNYV 58

Src Homology 3 domain of Small G protein Signaling Modulator 3; SGSM3 is also called Merlin-associated protein (MAP), RUN and SH3 domain-containing protein (RUSC3), RUN and TBC1 domain-containing protein 3 (RUTBC3), Rab GTPase-activating protein 5 (RabGAP5), or Rab GAP-like protein (RabGAPLP). It is expressed ubiquitously and functions as a regulator of small G protein RAP- and RAB-mediated neuronal signaling. It is involved in modulating NGF-mediated neurite outgrowth and differentiation. It also interacts with the tumor suppressor merlin and may play a role in the merlin-associated suppression of cell growth. SGSM3 contains TBC, SH3, and RUN domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212747 Cd Length: 53 Bit Score: 50.58 E-value: 5.57e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVL-EKQENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11813     1 RAKALLDFERHDDDELGFRKNDIITIIsQKDEHCWVGELNGLRGWFPAKFVEL 53

Src Homology 3 domain of Sdc25/Cdc25 guanine nucleotide exchange factors; This subfamily is composed of the Saccharomyces cerevisiae guanine nucleotide exchange factors (GEFs) Sdc25 and Cdc25, and similar proteins. These GEFs regulate Ras by stimulating the GDP/GTP exchange on Ras. Cdc25 is involved in the Ras/PKA pathway that plays an important role in the regulation of metabolism, stress responses, and proliferation, depending on available nutrients and conditions. Proteins in this subfamily contain an N-terminal SH3 domain as well as REM (Ras exchanger motif) and RasGEF domains at the C-terminus. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212816 Cd Length: 55 Bit Score: 50.36 E-value: 6.43e-08

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 688602146 1009 PATTPEQLSLTPGQLIVVLHKNSNSWWLGELQARGKKRKKGWFQSS 1054
Cdd:cd11883     9 TPKSKNQLSFKAGDIIYVLNKDPSGWWDGVIISSSGKVKRGWFPSN 54

C2 domain second repeat present in RasA1 and RasA4; RasA1 and RasA4 are GAP1s (GTPase activating protein 1s ), Ras-specific GAP members, which suppresses Ras function by enhancing the GTPase activity of Ras proteins resulting in the inactive GDP-bound form of Ras. In this way it can control cellular proliferation and differentiation. Both proteins contain two C2 domains, a Ras-GAP domain, a plextrin homology (PH)-like domain, and a Bruton's Tyrosine Kinase (BTK) zinc binding domain. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 175991 [Multi-domain] Cd Length: 123 Bit Score: 52.87 E-value: 6.58e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1512 RLLVTVLEATELKPCKPNGKSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQFSPDDFLG 1591
Cdd:cd04025     1 RLRCHVLEARDLAPKDRNGTSDPFVRVFYNGQTLETSVVKKSCYPRWNEVFEFELMEGADSPLSVEVWDWDLVSKNDFLG 80

                          90
                  ....*....|....*..
gi 688602146 1592 RTEVPVATIKKDQDGKG 1608
Cdd:cd04025    81 KVVFSIQTLQQAKQEEG 97

Second Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212834 [Multi-domain] Cd Length: 55 Bit Score: 50.42 E-value: 6.72e-08

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                  ....*....|....*....|....*....|....*....|....*.
gi 688602146 1080 YDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11901     8 FNYTAEREDELSLVKGTKVIVMEKCSDGWWRGSYNGQVGWFPSNYV 53

Src homology 3 domain of eumetazoan Actin-binding protein 1; Abp1, also called drebrin-like protein, is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a helical domain, and a C-terminal SH3 domain. Mammalian Abp1, unlike yeast Abp1, does not contain an acidic domain that interacts with the Arp2/3 complex. It regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. Abp1 deficiency causes abnormal organ structure and function of the spleen, heart, and lung of mice. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212893 [Multi-domain] Cd Length: 54 Bit Score: 50.48 E-value: 7.03e-08

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                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEK--EGeWWRGCIGDQT-GLFPSNYVK 983
Cdd:cd11960     4 ALYDYQAADDTEISFDPGDIITDIEQidEG-WWRGTGPDGTyGLFPANYVE 53

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 429575 [Multi-domain] Cd Length: 54 Bit Score: 50.29 E-value: 8.41e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 688602146   934 YVALYTYESPESGDLTFSAEDVVLVTEKE-GEWWRGCIGDQTGLFPSNYVKP 984
Cdd:pfam07653    2 GRVIFDYVGTDKNGLTLKKGDVVKVLGKDnDGWWEGETGGRVGLVPSTAVEE 53

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212757 [Multi-domain] Cd Length: 53 Bit Score: 50.03 E-value: 8.93e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQEN-WWYGELKEKRGWFPCSHVSV 905
Cdd:cd11823     1 RCKALYSYTANREDELSLQPGDIIEVHEKQDDgWWLGELNGKKGIFPATYVEE 53

Fifth Src homology 3 domain (or SH3E) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212929 [Multi-domain] Cd Length: 54 Bit Score: 49.98 E-value: 9.12e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEKEG-EWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11996     2 QVIAMYDYTANNEDELSFSKGQLINVLNKDDpDWWQGEINGVTGLFPSNYVK 53

Second Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212749 [Multi-domain] Cd Length: 52 Bit Score: 49.87 E-value: 9.81e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11815     3 VVLHDFPAEHSDDLSLNSGEIVYLLEKIDTEWYRGKCKNTTGIFPANHVK 52

Src Homology 3 domain of Amphiphysin and related domains; Amphiphysins function primarily in endocytosis and other membrane remodeling events. They exist in several isoforms and mammals possess two amphiphysin proteins from distinct genes. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin, and synaptojanin. They function in synaptic vesicle endocytosis. Human autoantibodies to amphiphysin I hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy. Amphiphysins contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. The SH3 domain of amphiphysins bind proline-rich motifs present in binding partners such as dynamin, synaptojanin, and nsP3. It also belongs to a subset of SH3 domains that bind ubiquitin in a site that overlaps with the peptide binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212724 [Multi-domain] Cd Length: 64 Bit Score: 50.40 E-value: 9.99e-08

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                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1073 LCQVIAMYDYKAANKDEMSFQKGQLITVLNKDNPD-----WWKG--EVAGVTGLFPTNYVK 1126
Cdd:cd11790     2 LYKVRATHDYTAEDTDELTFEKGDVILVIPFDDPEeqdegWLMGvkESTGCRGVFPENFTE 62

Second Src Homology 3 domain (SH3B) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CIN85. SH3B has been shown to bind Cbl proline-rich peptides and ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212988 [Multi-domain] Cd Length: 53 Bit Score: 49.99 E-value: 1.02e-07

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                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1074 CQViaMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12055     2 CQV--AFSYLPQNEDELELKVGDIIEVVGEVEEGWWEGVLNGKTGMFPSNFIK 52

First Src Homology 3 domain of SH3 domain containing ring finger protein 1, an E3 ubiquitin-protein ligase; SH3RF1 is also called POSH (Plenty of SH3s) or SH3MD2 (SH3 multiple domains protein 2). It is a scaffold protein that acts as an E3 ubiquitin-protein ligase. It plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. It contains an N-terminal RING finger domain and four SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212860 Cd Length: 54 Bit Score: 49.95 E-value: 1.05e-07

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                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11927     5 ALYNYEGKEPGDLKFSKGDIIILRRQVDENWYHGEVNGIHGFFPTNFVQI 54

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 1 (PACSIN1) and PACSIN 2; PACSIN 1 or Syndapin I (Synaptic dynamin-associated protein I) is expressed specifically in the brain and is localized in neurites and synaptic boutons. It binds the brain-specific proteins dynamin I, synaptojanin, synapsin I, and neural Wiskott-Aldrich syndrome protein (nWASP), and functions as a link between the cytoskeletal machinery and synaptic vesicle endocytosis. PACSIN 1 interacts with huntingtin and may be implicated in the neuropathology of Huntington's disease. PACSIN 2 or Syndapin II is expressed ubiquitously and is involved in the regulation of tubulin polymerization. It associates with Golgi membranes and forms a complex with dynamin II which is crucial in promoting vesicle formation from the trans-Golgi network. PACSINs act as regulators of cytoskeletal and membrane dynamics. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212931 [Multi-domain] Cd Length: 56 Bit Score: 49.95 E-value: 1.13e-07

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                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKG-QLITVLNKDNPDWWKGEV-AGVTGLFPTNYVK 1126
Cdd:cd11998     2 RVRALYDYDGQEQDELSFKAGdELTKLEDEDEQGWCKGRLdSGQVGLYPANYVE 55

First Src Homology 3 domain of SH3 domain containing ring finger 2; SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal RING finger domain and three SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212862 Cd Length: 54 Bit Score: 49.94 E-value: 1.14e-07

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                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11929     5 ALCNYRGHNPGDLKFNKGDVILLRRQLDENWYLGEINGVSGIFPASSVEV 54

First Src Homology 3 domain (SH3A) of CD2-associated protein and similar proteins; This subfamily is composed of the first SH3 domain (SH3A) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3A of both proteins bind to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic domain of the cell adhesion protein CD2. CIN85 SH3A binds to internal proline-rich motifs within the proline-rich region; this intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. CIN85 SH3A has also been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212806 [Multi-domain] Cd Length: 53 Bit Score: 49.96 E-value: 1.14e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVL-VTEKEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11873     1 EVIVEFDYDAEEPDELTLKVGDIITnVKKMEEGWWEGTLNGKRGMFPDNFVK 52

N-terminal Src Homology 3 domain of Ct10 Regulator of Kinase adaptor proteins; CRK adaptor proteins consists of SH2 and SH3 domains, which bind tyrosine-phosphorylated peptides and proline-rich motifs, respectively. They function downstream of protein tyrosine kinases in many signaling pathways started by various extracellular signals, including growth and differentiation factors. Cellular CRK (c-CRK) contains a single SH2 domain, followed by N-terminal and C-terminal SH3 domains. It is involved in the regulation of many cellular processes including cell growth, motility, adhesion, and apoptosis. CRK has been implicated in the malignancy of various human cancers. The N-terminal SH3 domain of CRK binds a number of target proteins including DOCK180, C3G, SOS, and cABL. The CRK family includes two alternatively spliced protein forms, CRKI and CRKII, that are expressed by the CRK gene, and the CRK-like (CRKL) protein, which is expressed by a distinct gene (CRKL). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212692 [Multi-domain] Cd Length: 55 Bit Score: 49.67 E-value: 1.16e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVA-GVTGLFPTNYV 1125
Cdd:cd11758     3 VRALFDFPGNDDEDLPFKKGEILTVIRKPEEQWWNARNSeGKTGMIPVPYV 53

Second Src Homology 3 domain (SH3B) of CD2-associated protein and similar proteins; This subfamily is composed of the second SH3 domain (SH3B) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3B of both proteins have been shown to bind to Cbl. In the case of CD2AP, its SH3B binds to Cbl at a site distinct from the c-Cbl/SH3A binding site. The CIN85 SH3B also binds ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212807 [Multi-domain] Cd Length: 53 Bit Score: 49.64 E-value: 1.22e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYeSPESGD-LTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11874     4 VLFSY-TPQNEDeLELKVGDTIEVLGEVEEgWWEGKLNGKVGVFPSNFVK 52

Src Homology 3 domain of Mixed Lineage Kinases; MLKs are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Mammals have four MLKs (MLK1-4), mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212809 [Multi-domain] Cd Length: 58 Bit Score: 49.82 E-value: 1.25e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGE------WWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11876     2 WTALFDYDARGEDELTLRRGQPVEVLSKDAAvsgdegWWTGKIGDKVGIFPSNYVAP 58

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212700 [Multi-domain] Cd Length: 53 Bit Score: 49.57 E-value: 1.42e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRG-CIGdQTGLFPSNYV 982
Cdd:cd11766     1 PAVVKFNYEAQREDELSLRKGDRVLVLEKSSDgWWRGeCNG-QVGWFPSNYV 51

Src Homology 3 domain of Sorting Nexin 9 and similar proteins; Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. This subfamily consists of SH3 domain containing SNXs including SNX9, SNX18, SNX33, and similar proteins. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212697 [Multi-domain] Cd Length: 55 Bit Score: 49.63 E-value: 1.52e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTVrETGWLYGSYS-GNRGWFPESYAE 804
Cdd:cd11763     2 VRALYDFDSQPSGELSLRAGEVLTITRQDV-GDGWLEGRNSrGEVGLFPSSYVE 54

C-terminal Src Homology 3 domain of NADPH oxidase activator 1; Noxa1 is a homolog of p67phox and is a cytosolic subunit of the nonphagocytic NADPH oxidase complex Nox1, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Noxa1 is co-expressed with Nox1 in colon, stomach, uterus, prostate, and vascular smooth muscle cells, consistent with its regulatory role. It does not interact with p40phox, unlike p67phox, making Nox1 activity independent of p40phox, unlike Nox2. Noxa1 contains TPR, PB1, and C-terminal SH3 domains, but lacks the central SH3 domain that is present in p67phox. The TPR domain binds activated GTP-bound Rac. The C-terminal SH3 domain binds the polyproline motif found at the C-terminus of Noxo1, a homolog of p47phox. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212980 Cd Length: 53 Bit Score: 49.43 E-value: 1.55e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd12047     1 RMVAQHDYSAQGPEDLEFSQGDTIDILSEVNQEWLEGHCDGRIGIFPKCFA 51

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase 2; GRAF2, also called Rho GTPase activating protein 10 (ARHGAP10) or PS-GAP, is a GAP with activity towards Cdc42 and RhoA. It regulates caspase-activated p21-activated protein kinase-2 (PAK-2p34). GRAF2 interacts with PAK-2p34, leading to its stabilization and decrease of cell death. It is highly expressed in skeletal muscle, and is involved in alpha-catenin recruitment at cell-cell junctions. GRAF2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212998 [Multi-domain] Cd Length: 54 Bit Score: 49.60 E-value: 1.60e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  753 RALYPFTARNSDELTLEADCFIQvDESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd12065     3 KAVYPCEAEHSSELSFEVGAIFE-DVTLSREPGWLEGTLNGKRGLIPENYVE 53

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212790 [Multi-domain] Cd Length: 53 Bit Score: 49.17 E-value: 1.65e-07

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLEKQEN-WWYGELKEKRGWFPCSH 902
Cdd:cd11856     3 VAIADYEAQGDDEISLQEGEVVEVLEKNDSgWWYVRKGDKEGWVPASY 50

Src homology 3 domain of Yes Protein Tyrosine Kinase; Yes (or c-Yes) is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. c-Yes kinase is the cellular homolog of the oncogenic protein (v-Yes) encoded by the Yamaguchi 73 and Esh sarcoma viruses. It displays functional overlap with other Src subfamily members, particularly Src. It also shows some unique functions such as binding to occludins, transmembrane proteins that regulate extracellular interactions in tight junctions. Yes also associates with a number of proteins in different cell types that Src does not interact with, like JAK2 and gp130 in pre-adipocytes, and Pyk2 in treated pulmonary vein endothelial cells. Although the biological function of Yes remains unclear, it appears to have a role in regulating cell-cell interactions and vesicle trafficking in polarized cells. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212940 [Multi-domain] Cd Length: 58 Bit Score: 49.65 E-value: 1.69e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  934 YVALYTYESPESGDLTF-SAEDVVLVTEKEGEWW--RGCIGDQTGLFPSNYVKPKE 986
Cdd:cd12007     3 FVALYDYEARTTEDLSFkKGERFQIINNTEGDWWeaRSIATGKNGYIPSNYVAPAD 58

Second Src homology 3 domain of Rab3-interacting molecules (RIMs) binding proteins; RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2. RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3. RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery. RIM-BPs contain three SH3 domains and two to three fibronectin III repeats. Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3. RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis. The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212945 Cd Length: 62 Bit Score: 49.60 E-value: 1.71e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 688602146 1077 IAMYDYKA--------ANKDEMSFQKGQLITVL-NKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12012     3 VALFDYDPltmspnpdAAEEELPFKEGQLIKVYgDKDADGFYLGEINGRRGLVPCNMVS 61

Src Homology 3 domain of Bbc1 and similar domains; This subfamily is composed of Saccharomyces cerevisiae Bbc1p, also called Mti1p (Myosin tail region-interacting protein), and similar proteins. Bbc1p interacts with and regulates type I myosins in yeast, Myo3p and Myo5p, which are involved in actin cytoskeletal reorganization. It also binds and inhibits Las17, a WASp family protein that functions as an activator of the Arp2/3 complex. Bbc1p contains an N-terminal SH3 domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212820 [Multi-domain] Cd Length: 60 Bit Score: 49.65 E-value: 1.75e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKE-GEWWRGCIGD-----QTGLFPSNYVKP 984
Cdd:cd11887     5 KALYPYESDHEDDLNFDVGQLITVTEEEdADWYFGEYVDsngntKEGIFPKNFVEV 60

First Src homology 3 domain (or SH3A) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212770 [Multi-domain] Cd Length: 55 Bit Score: 49.28 E-value: 1.79e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLEKQEN---WWYGELKEKRGWFPCSHVS 904
Cdd:cd11836     4 ALYAFEARNPDEISFQPGDIIQVDESQVAepgWLAGELKGKTGWFPANYVE 54

chromosome segregation protein SMC, primarily archaeal type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. It is found in a single copy and is homodimeric in prokaryotes, but six paralogs (excluded from this family) are found in eukarotes, where SMC proteins are heterodimeric. This family represents the SMC protein of archaea and a few bacteria (Aquifex, Synechocystis, etc); the SMC of other bacteria is described by TIGR02168. The N- and C-terminal domains of this protein are well conserved, but the central hinge region is skewed in composition and highly divergent. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

Pssm-ID: 274009 [Multi-domain] Cd Length: 1164 Bit Score: 56.23 E-value: 1.90e-07

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   452 SKRVELQTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRQGQWAELELINQRrdvcitdINSLQLQF 531
Cdd:TIGR02169  840 EQRIDLKEQIKSIEKEIENLNGKKEELEEELEELEAALRDLESRLGDLKKERDELEAQLRELERK-------IEELEAQI 912

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   532 DEMQRQLNQLGPEKQRLADRLVHFTQNISS--------PLINDVKQSVCEKDRSCRKL---------------------K 582
Cdd:TIGR02169  913 EKKRKRLSELKAKLEALEEELSEIEDPKGEdeeipeeeLSLEDVQAELQRVEEEIRALepvnmlaiqeyeevlkrldelK 992

                          170       180
                   ....*....|....*....|....*.
gi 688602146   583 EQLDVLERETTAKLSQMEQYNKEIKE 608
Cdd:TIGR02169  993 EKRAKLEEERKAILERIEEYEKKKRE 1018

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212808 [Multi-domain] Cd Length: 55 Bit Score: 49.27 E-value: 1.91e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11875     1 KARVLFDYEAENEDELTLREGDIVTILSKDCEDKGWWKGELNGKRGVFPDNFVE 54

First Src Homology 3 domain of SH3 domain containing ring finger proteins; This model represents the first SH3 domain of SH3RF1 (or POSH), SH3RF2 (or POSHER), SH3RF3 (POSH2), and similar domains. Members of this family are scaffold proteins that function as E3 ubiquitin-protein ligases. They all contain an N-terminal RING finger domain and multiple SH3 domains; SH3RF1 and SH3RF3 have four SH3 domains while SH3RF2 has three. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3RF2 acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212720 [Multi-domain] Cd Length: 53 Bit Score: 49.28 E-value: 1.95e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIItVLEKQ--ENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11786     2 AKALYNYEGKEPGDLSFKKGDII-LLRKRidENWYHGECNGKQGFFPASYVQV 53

Src Homology 3 domain of beta-Pak Interactive eXchange factor; Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212994 [Multi-domain] Cd Length: 54 Bit Score: 49.30 E-value: 2.13e-07

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVT-EKEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd12061     4 AKFNFQQTNEDELSFSKGDVIHVTrVEEGGWWEGTHNGRTGWFPSNYVR 52

Src Homology 3 domain of Nephrocystin (or Nephrocystin-1); Nephrocystin contains an SH3 domain involved in signaling pathways that regulate cell adhesion and cytoskeletal organization. It is a protein that in humans is associated with juvenile nephronophthisis, an inherited kidney disease characterized by renal fibrosis that lead to chronic renal failure in children. It is localized in cell-cell junctions in renal duct cells, and is known to interact with Ack1, an activated Cdc42-associated kinase. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212704 [Multi-domain] Cd Length: 54 Bit Score: 48.85 E-value: 2.26e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVA-GVTGLFPTNYVKM 1127
Cdd:cd11770     2 YEALSDFQAEQEGDLSFKKGEVLRIISKRADGWWLAENSkGNRGLVPKTYLKV 54

Third Src Homology 3 domain of SH3 domain containing ring finger 2; SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal RING finger domain and three SH3 domains. This model represents the third SH3 domain, located in the middle, of SH3RF2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212718 Cd Length: 55 Bit Score: 49.01 E-value: 2.63e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGE--VAGVTGLFPTNYV 1125
Cdd:cd11784     3 VALHSYSAHRPEELELQKGEGVRVLGKFQEGWLRGLslVTGRVGIFPSNYV 53

First Src Homology 3 domain (SH3A) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CD2AP. SH3A binds to the PXXXPR motif present in c-Cbl and the cytoplasmic domain of cell adhesion protein CD2. Its interaction with CD2 anchors CD2 at sites of cell contact. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212986 Cd Length: 56 Bit Score: 49.07 E-value: 2.63e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPD-WWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12053     1 EYIVEYDYDAVHEDELTIRVGEIIRNVKKLEEEgWLEGELNGRRGMFPDNFVK 53

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 1 (PACSIN1) and PACSIN 2; PACSIN 1 or Syndapin I (Synaptic dynamin-associated protein I) is expressed specifically in the brain and is localized in neurites and synaptic boutons. It binds the brain-specific proteins dynamin I, synaptojanin, synapsin I, and neural Wiskott-Aldrich syndrome protein (nWASP), and functions as a link between the cytoskeletal machinery and synaptic vesicle endocytosis. PACSIN 1 interacts with huntingtin and may be implicated in the neuropathology of Huntington's disease. PACSIN 2 or Syndapin II is expressed ubiquitously and is involved in the regulation of tubulin polymerization. It associates with Golgi membranes and forms a complex with dynamin II which is crucial in promoting vesicle formation from the trans-Golgi network. PACSINs act as regulators of cytoskeletal and membrane dynamics. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212931 [Multi-domain] Cd Length: 56 Bit Score: 48.79 E-value: 2.86e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE--WWRGCI-GDQTGLFPSNYVKP 984
Cdd:cd11998     5 ALYDYDGQEQDELSFKAGDELTKLEDEDEqgWCKGRLdSGQVGLYPANYVEP 56

Fourth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212751 [Multi-domain] Cd Length: 50 Bit Score: 48.24 E-value: 3.28e-07

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNY 981
Cdd:cd11817     3 VALYDFTGETEEDLSFQRGDRILVTEHlDAEWSRGRLNGREGIFPRAF 50

Src Homology 3 domain of Myosin XV; This subfamily is composed of proteins with similarity to Myosin XVa. Myosin XVa is an unconventional myosin that is critical for the normal growth of mechanosensory stereocilia of inner ear hair cells. Mutations in the myosin XVa gene are associated with nonsyndromic hearing loss. Myosin XVa contains a unique N-terminal extension followed by a motor domain, light chain-binding IQ motifs, and a tail consisting of a pair of MyTH4-FERM tandems separated by a SH3 domain, and a PDZ domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212817 [Multi-domain] Cd Length: 56 Bit Score: 48.48 E-value: 3.42e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNK---DNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11884     2 VVAVRAYITRDQTLLSFHKGDVIKLLPKegpLDPGWLFGTLDGRSGAFPKEYV 54

C2 domain first repeat contained in Rab3-interacting molecule (RIM) proteins; RIMs are believed to organize specialized sites of the plasma membrane called active zones. They also play a role in controlling neurotransmitter release, plasticity processes, as well as memory and learning. RIM contains an N-terminal zinc finger domain, a PDZ domain, and two C-terminal C2 domains (C2A, C2B). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have a type-I topology and do not bind Ca2+.

Pssm-ID: 175997 [Multi-domain] Cd Length: 125 Bit Score: 50.71 E-value: 3.68e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKPCKPNGKSNPYceltmgAQCY-----------TSRHQPDTLNPKWSfncQFFI------KDLYQDV 1573
Cdd:cd04031    16 SQLIVTVLQARDLPPRDDGSLRNPY------VKVYllpdrsekskrRTKTVKKTLNPEWN---QTFEysnvrrETLKERT 86

                          90       100
                  ....*....|....*....|....*.
gi 688602146 1574 LCLTVFERDQFSPDDFLGRTEVPVAT 1599
Cdd:cd04031    87 LEVTVWDYDRDGENDFLGEVVIDLAD 112

Src homology 3 domain of Signal Transducing Adaptor Molecule 2; STAM2, also called EAST (Epidermal growth factor receptor-associated protein with SH3 and TAM domain) or Hbp (Hrs binding protein), is part of the endosomal sorting complex required for transport (ESCRT-0). It plays a role in sorting mono-ubiquinated endosomal cargo for trafficking to the lysosome for degradation. It is also involved in the regulation of exocytosis. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212896 [Multi-domain] Cd Length: 57 Bit Score: 48.48 E-value: 3.75e-07

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  936 ALYTYESPESGDLTF-SAEDVVLVTEKEGEWWRGCIGDQTGLFPSNYV 982
Cdd:cd11963     6 ALYDFEAVEDNELTFkHGEIIIVLDDSDANWWKGENHRGVGLFPSNFV 53

C-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also has roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRAP2 binds to different motifs found in substrate peptides including the typical PxxP motif in hematopoietic progenitor kinase 1 (HPK1), the RxxK motif in SLP-76 and HPK1, and the RxxxxK motif in phosphatase-like protein HD-PTP. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212883 [Multi-domain] Cd Length: 53 Bit Score: 48.28 E-value: 3.94e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11950     4 ALYDFEALEDDELGFNSGDVIEVLDSsNPSWWKGRLHGKLGLFPANYVAP 53

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212746 [Multi-domain] Cd Length: 52 Bit Score: 48.28 E-value: 3.98e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGD-QTGLFPSNYV 982
Cdd:cd11812     3 VALYDYTANRSDELTIHRGDIIRVLYKDNDnWWFGSLVNgQQGYFPANYV 52

Src homology 3 domain of Src kinase-like Protein Tyrosine Kinases; Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, Yes, and Brk. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Src kinases are overexpressed in a variety of human cancers, making them attractive targets for therapy. They are also implicated in acute inflammatory responses and osteoclast function. Src, Fyn, Yes, and Yrk are widely expressed, while Blk, Lck, Hck, Fgr, Lyn, and Brk show a limited expression pattern. This subfamily also includes Drosophila Src42A, Src oncogene at 42A (also known as Dsrc41) which accumulates at sites of cell-cell or cell-matrix adhesion, and participates in Drosphila development and wound healing. It has been shown to promote tube elongation in the tracheal system, is essential for proper cell-cell matching during dorsal closure, and regulates cell-cell contacts in developing Drosophila eyes. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212779 [Multi-domain] Cd Length: 52 Bit Score: 48.35 E-value: 4.07e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGC--IGDQTGLFPSNY 981
Cdd:cd11845     2 YVALYDYEARTDDDLSFKKGDRLQILDDsDGDWWLARhlSTGKEGYIPSNY 52

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212808 [Multi-domain] Cd Length: 55 Bit Score: 48.12 E-value: 4.11e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  936 ALYTYEsPESGD-LTFSAEDVVLVTEKEGE---WWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11875     4 VLFDYE-AENEDeLTLREGDIVTILSKDCEdkgWWKGELNGKRGVFPDNFVEP 55

Src homology 3 domain of Ubiquitin-associated and SH3 domain-containing protein A; UBASH3A is also called Cbl-Interacting Protein 4 (CLIP4), T cell Ubiquitin LigAnd (TULA), or T cell receptor Signaling (STS)-2. It is only found in lymphoid cells and exhibits weak phosphatase activity. UBASH3A facilitates T cell-induced apoptosis through interaction with the apoptosis-inducing factor AIF. It is involved in regulating the level of phosphorylation of the zeta-associated protein (ZAP)-70 tyrosine kinase. TULA proteins contain an N-terminal UBA domain, a central SH3 domain, and a C-terminal histidine phosphatase domain. They bind c-Cbl through the SH3 domain and to ubiquitin via UBA. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212870 [Multi-domain] Cd Length: 60 Bit Score: 48.48 E-value: 4.27e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDESTVRET--GWLYGS--YSGNRGWFPESYAER 805
Cdd:cd11937     2 TLRALFQYKPQNIDELMLSPGDYIFVDPTQQSEAseGWVIGIshRTGCRGFLPENYTER 60

C2 domain first repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); plant subset; MCTPs are involved in Ca2+ signaling at the membrane. Plant-MCTPs are composed of a variable N-terminal sequence, four C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-II topology.

Pssm-ID: 175989 [Multi-domain] Cd Length: 127 Bit Score: 50.41 E-value: 4.27e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1512 RLLVTVLEATELKPCKPNGKSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFI---KDLYQDVLCLTVF-ERDQFSPD 1587
Cdd:cd04022     1 KLVVEVVDAQDLMPKDGQGSSSAYVELDFDGQKKRTRTKPKDLNPVWNEKLVFNVsdpSRLSNLVLEVYVYnDRRSGRRR 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 688602146 1588 DFLGRTEVPVATIKKDQDGKG---PLVRRLLLHEVpTGEVKVRL 1628
Cdd:cd04022    81 SFLGRVRISGTSFVPPSEAVVqryPLEKRGLFSRV-RGEIGLKV 123

Second Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212835 [Multi-domain] Cd Length: 55 Bit Score: 48.46 E-value: 4.29e-07

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 688602146 1080 YDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11902     7 FAYVAEREDELSLVKGSRVTVMEKCSDGWWRGSYNGQIGWFPSNYV 52

Src homology 3 domain of Slit-Robo GTPase Activating Proteins 1, 2, and 3; srGAP1, also called Rho GTPase-Activating Protein 13 (ARHGAP13), is a Cdc42- and RhoA-specific GAP and is expressed later in the development of central nervous system tissues. srGAP2 is expressed in zones of neuronal differentiation. It plays a role in the regeneration of neurons and axons. srGAP3, also called MEGAP (MEntal disorder associated GTPase-Activating Protein), is a Rho GAP with activity towards Rac1 and Cdc42. It impacts cell migration by regulating actin and microtubule cytoskeletal dynamics. The association between srGAP3 haploinsufficiency and mental retardation is under debate. srGAPs are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212888 [Multi-domain] Cd Length: 53 Bit Score: 48.02 E-value: 4.34e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11955     1 EAIAKFDYVGRSARELSFKKGASLLLYHRASDDWWEGRHNGIDGLVPHQYI 51

Second Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212749 [Multi-domain] Cd Length: 52 Bit Score: 47.95 E-value: 4.39e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11815     3 VVLHDFPAEHSDDLSLNSGEIVYLLEKiDTEWYRGKCKNTTGIFPANHVK 52

Fifth Src homology 3 domain (or SH3E) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212928 [Multi-domain] Cd Length: 54 Bit Score: 48.03 E-value: 4.59e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEKEG-EWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11995     2 QVIGMYDYTAQNDDELAFSKGQIINVLNKEDpDWWKGELNGQVGLFPSNYVK 53

Src homology 3 domain of Lck Protein Tyrosine Kinase; Lck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cells and natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212938 [Multi-domain] Cd Length: 54 Bit Score: 47.90 E-value: 5.49e-07

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gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDnPDWWKGE--VAGVTGLFPTNYVKM 1127
Cdd:cd12005     1 LVVALYSYEPSHDGDLGFEKGEKLRILEQS-GEWWKAQslTTGQEGFIPFNFVAK 54

Src homology 3 domain of Src Protein Tyrosine Kinase; Src (or c-Src) is a cytoplasmic (or non-receptor) PTK and is the vertebrate homolog of the oncogenic protein (v-Src) from Rous sarcoma virus. Together with other Src subfamily proteins, it is involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. Src also play a role in regulating cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Elevated levels of Src kinase activity have been reported in a variety of human cancers. Several inhibitors of Src have been developed as anti-cancer drugs. Src is also implicated in acute inflammatory responses and osteoclast function. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212941 [Multi-domain] Cd Length: 56 Bit Score: 47.80 E-value: 5.65e-07

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gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGE--VAGVTGLFPTNYV 1125
Cdd:cd12008     3 VALYDYESRTETDLSFKKGERLQIVNNTEGDWWLAHslTTGQTGYIPSNYV 53

C2 domain second repeat present in Rabphilin and Double C2 domain; Rabphilin is found neurons and in neuroendrocrine cells, while Doc2 is found not only in the brain but in tissues, including mast cells, chromaffin cells, and osteoblasts. Rabphilin and Doc2s share highly homologous tandem C2 domains, although their N-terminal structures are completely different: rabphilin contains an N-terminal Rab-binding domain (RBD),7 whereas Doc2 contains an N-terminal Munc13-1-interacting domain (MID). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 176030 [Multi-domain] Cd Length: 133 Bit Score: 50.42 E-value: 5.71e-07

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gi 688602146 1511 GRLLVTVLEATELKPCKPNGKSNPYCELTM-----GAQCYTSRHQPDTLNPKWsfNCQFFI----KDLYQDVLCLTVFER 1581
Cdd:cd08384    13 RGLIVGIIRCVNLAAMDANGYSDPFVKLYLkpdagKKSKHKTQVKKKTLNPEF--NEEFFYdikhSDLAKKTLEITVWDK 90

                          90
                  ....*....|
gi 688602146 1582 DQFSPDDFLG 1591
Cdd:cd08384    91 DIGKSNDYIG 100

Src homology 3 domain of Fyn and Yrk Protein Tyrosine Kinases; Fyn and Yrk (Yes-related kinase) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Fyn, together with Lck, plays a critical role in T-cell signal transduction by phosphorylating ITAM (immunoreceptor tyr activation motif) sequences on T-cell receptors, ultimately leading to the proliferation and differentiation of T-cells. In addition, Fyn is involved in the myelination of neurons, and is implicated in Alzheimer's and Parkinson's diseases. Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212939 [Multi-domain] Cd Length: 56 Bit Score: 48.12 E-value: 5.79e-07

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gi 688602146  934 YVALYTYESPESGDLTF-SAEDVVLVTEKEGEWW--RGCIGDQTGLFPSNYVKP 984
Cdd:cd12006     3 FVALYDYEARTEDDLSFhKGEKFQILNSSEGDWWeaRSLTTGETGYIPSNYVAP 56

C-terminal (or second) Src Homology 3 domain of the p67phox subunit of NADPH oxidase; p67phox, also called Neutrophil cytosol factor 2 (NCF-2), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox plays a regulatory role and contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. It binds, via its C-terminal SH3 domain, to a proline-rich region of p47phox and upon activation, this complex assembles with flavocytochrome b558, the Nox2-p22phox heterodimer. Concurrently, RacGTP translocates to the membrane and interacts with the TPR domain of p67phox, which leads to the activation of NADPH oxidase. The PB1 domain of p67phox binds to its partner PB1 domain in p40phox, and this facilitates the assembly of p47phox-p67phox at the membrane. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212979 [Multi-domain] Cd Length: 53 Bit Score: 47.87 E-value: 5.88e-07

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gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd12046     3 VALFSYEASQPEDLEFQKGDVILVLSKvNEDWLEGQCKGKIGIFPSAFVED 53

Second Src Homology 3 domain of Vinexin, also called Sorbin and SH3 domain containing 3 (Sorbs3); Vinexin is also called Sorbs3, SH3P3, and SH3-containing adapter molecule 1 (SCAM-1). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. Vinexin was first identified as a vinculin binding protein; it is co-localized with vinculin at cell-ECM and cell-cell adhesion sites. There are several splice variants of vinexin: alpha, which contains the SoHo and three SH3 domains and displays tissue-specific expression; and beta, which contains only the three SH3 domains and is widely expressed. Vinexin alpha stimulates the accumulation of F-actin at focal contact sites. Vinexin also promotes keratinocyte migration and wound healing. The SH3 domains of vinexin have been reported to bind a number of ligands including vinculin, WAVE2, DLG5, Abl, and Cbl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212857 Cd Length: 56 Bit Score: 47.65 E-value: 6.45e-07

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gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVT--GLFPTNYVKM 1127
Cdd:cd11924     2 EAVAQYTFKGDLEVELSFRKGEHICLIRKVNENWYEGRITGTGrqGIFPASYVQV 56

Second Src homology 3 domain of Tyrosine kinase substrate with four SH3 domains; Tks4, also called SH3 and PX domain-containing protein 2B (SH3PXD2B) or HOFI, is a Src substrate and scaffolding protein that plays an important role in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. It is required in the formation of functional podosomes, EGF-induced membrane ruffling, and lamellipodia generation. It plays an important role in cellular attachment and cell spreading. Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. It contains an N-terminal Phox homology (PX) domain and four SH3 domains. This model characterizes the second SH3 domain of Tks4. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213009 [Multi-domain] Cd Length: 54 Bit Score: 47.72 E-value: 6.51e-07

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gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12076     4 TVIYPYTARDQDEINLEKGAVVEVIQKNLEGWWKIRYQGKEGWAPASYLK 53

Second Src Homology 3 domain of Sorbin and SH3 domain containing 1 (Sorbs1), also called ponsin; Sorbs1 is also called ponsin, SH3P12, or CAP (c-Cbl associated protein). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It binds Cbl and plays a major role in regulating the insulin signaling pathway by enhancing insulin-induced phosphorylation of Cbl. Sorbs1, like vinexin, localizes at cell-ECM and cell-cell adhesion sites where it binds vinculin, paxillin, and afadin. It may function in the control of cell motility. Other interaction partners of Sorbs1 include c-Abl, Sos, flotillin, Grb4, ataxin-7, filamin C, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212855 [Multi-domain] Cd Length: 58 Bit Score: 47.68 E-value: 6.73e-07

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gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVT--GLFPTNYVKM 1127
Cdd:cd11922     2 EAIAKFNFNGDTQVEMSFRKGERITLLRQVDENWYEGRIPGTSrqGIFPITYVDV 56

Src homology 3 domain of Phospholipase C (PLC) gamma; PLC catalyzes the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG) in response to various receptors. Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma catalyzes this reaction in tyrosine kinase-dependent signaling pathways. It is activated and recruited to its substrate at the membrane. Vertebrates contain two forms of PLCgamma, PLCgamma1, which is widely expressed, and PLCgamma2, which is primarily found in haematopoietic cells. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212759 [Multi-domain] Cd Length: 54 Bit Score: 47.71 E-value: 6.82e-07

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gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLEKQEN-WWYGEL-KEKRGWFPCSHV 903
Cdd:cd11825     4 ALYDYRAQRPDELSFCKHAIITNVEKEDGgWWRGDYgGKKQKWFPANYV 52

Src homology 3 domain of ARHGEF9-like Rho guanine nucleotide exchange factors; Members of this family contain a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. They include the Rho guanine nucleotide exchange factors ARHGEF9, ASEF (also called ARHGEF4), ASEF2, and similar proteins. GEFs activate small GTPases by exchanging bound GDP for free GTP. ARHGEF9 specifically activates Cdc42, while both ASEF and ASEF2 can activate Rac1 and Cdc42. ARHGEF9 is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. ASEF plays a role in angiogenesis and cell migration. ASEF2 is important in cell migration and adhesion dynamics. ASEF exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli), leading to the activation of Rac1 or Cdc42. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212762 [Multi-domain] Cd Length: 53 Bit Score: 47.38 E-value: 7.36e-07

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gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTE-KEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11828     4 ALWDHVTMDPEELGFKAGDVIEVLDmSDKDWWWGSIRDEEGWFPASFVR 52

Third N-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin and key regulatory proteins of the actin cytoskeleton. It plays an important role in regulating cell junction configuration. The four N-terminal SH3 domains of DNMBP binds the GTPase dynamin, which plays an important role in the fission of endocytic vesicles. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212730 Cd Length: 51 Bit Score: 47.35 E-value: 7.41e-07

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gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11796     1 QARVLQDLSAQLDEELDLREGDVVTITGILDKGWFRGELNGRRGIFPEGFV 51

C-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also has roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRAP2 binds to different motifs found in substrate peptides including the typical PxxP motif in hematopoietic progenitor kinase 1 (HPK1), the RxxK motif in SLP-76 and HPK1, and the RxxxxK motif in phosphatase-like protein HD-PTP. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212883 [Multi-domain] Cd Length: 53 Bit Score: 47.51 E-value: 7.46e-07

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gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKEKRGWFPCSHV 903
Cdd:cd11950     1 QVRALYDFEALEDDELGFNSGDVIEVLDSSNpSWWKGRLHGKLGLFPANYV 51

First Src Homology 3 domain of Sorbin and SH3 domain containing 1 (Sorbs1), also called ponsin; Sorbs1 is also called ponsin, SH3P12, or CAP (c-Cbl associated protein). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It binds Cbl and plays a major role in regulating the insulin signaling pathway by enhancing insulin-induced phosphorylation of Cbl. Sorbs1, like vinexin, localizes at cell-ECM and cell-cell adhesion sites where it binds vinculin, paxillin, and afadin. It may function in the control of cell motility. Other interaction partners of Sorbs1 include c-Abl, Sos, flotillin, Grb4, ataxin-7, filamin C, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212852 [Multi-domain] Cd Length: 55 Bit Score: 47.65 E-value: 7.57e-07

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gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11919     2 PARAKFDFKAQTLKELPLQKGDIVYIYKQIDQNWYEGEHHGRVGIFPRSYIEL 54

Src Homology 3 domain of Mixed Lineage Kinases 1, 2, and 3; MLKs 1, 2, and 3 are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Little is known about the specific function of MLK1, also called MAP3K9. It is capable of activating the c-Jun N-terminal kinase pathway. Mice lacking both MLK1 and MLK2 are viable, fertile, and have normal life spans. MLK2, also called MAP3K10, is abundant in brain, skeletal muscle, and testis. It functions upstream of the MAPK, c-Jun N-terminal kinase. It binds hippocalcin, a calcium-sensor protein that protects neurons against calcium-induced cell death. Both MLK2 and hippocalcin may be associated with the pathogenesis of Parkinson's disease. MLK3, also called MAP3K11, is highly expressed in breast cancer cells and its signaling through c-Jun N-terminal kinase has been implicated in the migration, invasion, and malignancy of cancer cells. It also functions as a negative regulator of Inhibitor of Nuclear Factor-KappaB Kinase (IKK) and thus, impacts inflammation and immunity. MLKs contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212992 [Multi-domain] Cd Length: 58 Bit Score: 47.45 E-value: 7.71e-07

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gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGE------WWRGCIGDQTGLFPSNYVKP 984
Cdd:cd12059     2 WTAVFDYEASAEDELTLRRGDRVEVLSKDSAvsgdegWWTGKINDRVGIFPSNYVTS 58

Second Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the second SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212949 Cd Length: 54 Bit Score: 47.45 E-value: 8.31e-07

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gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12016     2 KYITTQAYKAENEDEIGFETGVVVEVIQKNLDGWWKIRYQGKEGWAPATYLK 53

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing protein 1; ASAP1 is also called DDEF1 (Development and Differentiation Enhancing Factor 1), AMAP1, centaurin beta-4, or PAG2. an Arf GTPase activating protein (GAP) with activity towards Arf1 and Arf5 but not Arf6. However, it has been shown to bind GTP-Arf6 stably without GAP activity. It has been implicated in cell growth, migration, and survival, as well as in tumor invasion and malignancy. It binds paxillin and cortactin, two components of invadopodia which are essential for tumor invasiveness. It also binds focal adhesion kinase (FAK) and the SH2/SH3 adaptor CrkL. ASAP1 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212898 [Multi-domain] Cd Length: 57 Bit Score: 47.31 E-value: 8.53e-07

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gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGV---TGLFPTNYVKM 1127
Cdd:cd11965     1 RVKTIYDCQADNDDELTFVEGEVIIVTGEEDQEWWIGHIEGQperKGVFPVSFVHI 56

Src homology 3 domain of Hematopoietic lineage cell-specific protein 1; HS1, also called HCLS1 (hematopoietic cell-specific Lyn substrate 1), is a cortactin homolog expressed specifically in hematopoietic cells. It is an actin regulatory protein that binds the Arp2/3 complex and stabilizes branched actin filaments. It is required for cell spreading and signaling in lymphocytes. It regulates cytoskeletal remodeling that controls lymphocyte trafficking, and it also affects tissue invasion and infiltration of leukemic B cells. Like cortactin, HS1 contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region binds the Arp2/3 complex and F-actin, while the C-terminal region acts as an adaptor or scaffold that can connect varied proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213006 [Multi-domain] Cd Length: 55 Bit Score: 47.52 E-value: 9.06e-07

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gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd12073     4 VALYDYQGEGDDEISFDPQETITDIEMVDEgWWKGTCHGHRGLFPANYVE 53

First Src homology 3 domain (or SH3A) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212770 [Multi-domain] Cd Length: 55 Bit Score: 47.35 E-value: 9.49e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEK---EGEWWRGCIGDQTGLFPSNYV 982
Cdd:cd11836     2 YRALYAFEARNPDEISFQPGDIIQVDESqvaEPGWLAGELKGKTGWFPANYV 53

Uncharacterized conserved protein YhaN, contains AAA domain [Function unknown];

Pssm-ID: 443752 [Multi-domain] Cd Length: 641 Bit Score: 53.62 E-value: 9.62e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  451 KSKRVELQTQKEKEQnDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRQ--GQWAELELINQRrdvcitdINSLQ 528
Cdd:COG4717    74 KELEEELKEAEEKEE-EYAELQEELEELEEELEELEAELEELREELEKLEKLLQllPLYQELEALEAE-------LAELP 145

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  529 LQFDEMQRQLNQLgpekQRLADRLVHFTQNIssplindvkqsvcekdrscRKLKEQLDVLERETT-AKLSQMEQYNKEIK 607
Cdd:COG4717   146 ERLEELEERLEEL----RELEEELEELEAEL-------------------AELQEELEELLEQLSlATEEELQDLAEELE 202

                         170       180
                  ....*....|....*....|....*....
gi 688602146  608 ELRQKQSQQQDVLEQLRRVRSDKLKELQR 636
Cdd:COG4717   203 ELQQRLAELEEELEEAQEELEELEEELEQ 231

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212746 [Multi-domain] Cd Length: 52 Bit Score: 47.12 E-value: 1.02e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGEL-KEKRGWFPCSHV 903
Cdd:cd11812     3 VALYDYTANRSDELTIHRGDIIRVLYKdNDNWWFGSLvNGQQGYFPANYV 52

Second Src homology 3 domain (or SH3B) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212922 [Multi-domain] Cd Length: 52 Bit Score: 47.02 E-value: 1.03e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPdWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11989     1 QAQALYPWRAKKDNHLNFNKNDVITVLEQQDM-WWFGEVQGQKGWFPKSYVKL 52

First Src Homology 3 domain of SH3 domain containing ring finger protein 1, an E3 ubiquitin-protein ligase; SH3RF1 is also called POSH (Plenty of SH3s) or SH3MD2 (SH3 multiple domains protein 2). It is a scaffold protein that acts as an E3 ubiquitin-protein ligase. It plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. It contains an N-terminal RING finger domain and four SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212860 Cd Length: 54 Bit Score: 47.25 E-value: 1.05e-06

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11927     5 ALYNYEGKEPGDLKFSKGDIIILRRQVDEnWYHGEVNGIHGFFPTNFVQ 53

Third Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle, of SH3RF3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212858 Cd Length: 57 Bit Score: 47.30 E-value: 1.07e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEV--AGVTGLFPTNYV 1125
Cdd:cd11925     4 LALYAYKPQKNDELELRKGEMYRVIEKCQDGWFKGTSlrTGVSGVFPGNYV 54

Src homology 3 domain of High osmolarity signaling protein Sho1p; Sho1p (or Sho1), also called SSU81 (Suppressor of SUA8-1 mutation), is a yeast membrane protein that regulates adaptation to high salt conditions by activating the HOG (high-osmolarity glycerol) pathway. High salt concentrations lead to the localization to the membrane of the MAPKK Pbs2, which is then activated by the MAPKK Ste11 and in turn, activates the MAPK Hog1. Pbs2 is localized to the membrane though the interaction of its PxxP motif with the SH3 domain of Sho1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212789 [Multi-domain] Cd Length: 55 Bit Score: 47.03 E-value: 1.10e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1078 AMYDYKAANKD--EMSFQKGQLITVlnKDNP-DWWKGEVA-GVTGLFPTNYVKM 1127
Cdd:cd11855     4 ALYPYDASPDDpnELSFEKGEILEV--SDTSgKWWQARKSnGETGICPSNYLQL 55

Uncharacterized protein, contains DUF3084 domain [Function unknown];

Pssm-ID: 443500 [Multi-domain] Cd Length: 370 Bit Score: 52.60 E-value: 1.18e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  469 QRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRQGQWAELELINQrrdvcitDINSLQLQFDEMQRQLNQLGPEKQRL 548
Cdd:COG4372     6 EKVGKARLSLFGLRPKTGILIAALSEQLRKALFELDKLQEELEQLRE-------ELEQAREELEQLEEELEQARSELEQL 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  549 ADRLvhftqnisspliNDVKQSVCEKDRSCRKLKEQLDVLERETTAKLSQMEQYNKEIKELRQKQSQQQDVLEQLRRVRS 628
Cdd:COG4372    79 EEEL------------EELNEQLQAAQAELAQAQEELESLQEEAEELQEELEELQKERQDLEQQRKQLEAQIAELQSEIA 146


                  ....*...
gi 688602146  629 DKLKELQR 636
Cdd:COG4372   147 EREEELKE 154

First Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The first SH3 domain of Nck proteins preferentially binds the PxxDY sequence, which is present in the CD3e cytoplasmic tail. This binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212699 [Multi-domain] Cd Length: 51 Bit Score: 47.03 E-value: 1.21e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNkDNPDWWKGE-VAGVTGLFPTNYV 1125
Cdd:cd11765     2 VVAKYDYTAQGDQELSIKKNEKLTLLD-DSKHWWKVQnSSNQTGYVPSNYV 51

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the Saccharomyces cerevisiae proteins, Ysc84p (also called LAS17-binding protein 4, Lsb4p) and Lsb3p, and similar fungal proteins. They contain an N-terminal SYLF domain (also called DUF500) and a C-terminal SH3 domain. Ysc84p localizes to actin patches and plays an important in actin polymerization during endocytosis. The N-terminal domain of both Ysc84p and Lsb3p can bind and bundle actin filaments. A study of the yeast SH3 domain interactome predicts that the SH3 domains of Lsb3p and Lsb4p may function as molecular hubs for the assembly of endocytic complexes. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212776 [Multi-domain] Cd Length: 55 Bit Score: 47.03 E-value: 1.24e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK---QENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11842     1 KAVALYDFAGEQPGDLAFQKGDIITILKKsdsQNDWWTGRIGGREGIFPANYVEL 55

Src Homology 3 domain of Apoptosis Stimulating of p53 protein 1; ASPP1, like ASPP2, activates the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73). In addition, it functions in the cytoplasm to regulate the nuclear localization of the transcriptional cofactors YAP and TAZ by inihibiting their phosphorylation; YAP and TAZ are important regulators of cell expansion, differentiation, migration, and invasion. ASPP1 is downregulated in breast tumors expressing wild-type p53. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of ASPP1 contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212887 [Multi-domain] Cd Length: 57 Bit Score: 46.94 E-value: 1.26e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLN-KDN--PDWWKGEVAGVTGLFPTN 1123
Cdd:cd11954     3 VYALWDYEAQNADELSFQEGDAITILRrKDDseTEWWWARLNDKEGYVPKN 53

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding proteins; CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes including migration, chemotaxis, apoptosis, differentiation, and progenitor cell function. They mediate the signaling of integrins at focal adhesions where they localize, and thus, regulate cell invasion and survival. Over-expression of these proteins is implicated in poor prognosis, increased metastasis, and resistance to chemotherapeutics in many cancers such as breast, lung, melanoma, and glioblastoma. CAS proteins have also been linked to the pathogenesis of inflammatory disorders, Alzheimer's, Parkinson's, and developmental defects. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. Vertebrates contain four CAS proteins: BCAR1 (or p130Cas), NEDD9 (or HEF1), EFS (or SIN), and CASS4 (or HEPL). The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212778 Cd Length: 56 Bit Score: 46.96 E-value: 1.36e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPD---WWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11844     4 ALYDNVAESPDELAFRRGDILTVLEQNTAGlegWWLCSLRGRQGIAPGNRLKL 56

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 3 (PACSIN3); PACSIN 3 or Syndapin III (Synaptic dynamin-associated protein III) is expressed ubiquitously and regulates glucose uptake in adipocytes through its role in GLUT1 trafficking. It also modulates the subcellular localization and stimulus-specific function of the cation channel TRPV4. PACSINs act as regulators of cytoskeletal and membrane dynamics. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212930 [Multi-domain] Cd Length: 56 Bit Score: 46.88 E-value: 1.36e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKG-QLITVLNKDNPDWWKGEV-AGVTGLFPTNYVK 1126
Cdd:cd11997     3 RVRALYDYTGQEADELSFKAGeELLKIGEEDEQGWCKGRLlSGRIGLYPANYVE 56

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

Pssm-ID: 212690 [Multi-domain] Cd Length: 51 Bit Score: 46.69 E-value: 1.42e-06

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 688602146 1010 ATTPEQLSLTPGQLIVVLHKNSNSWWLGELQargkKRKKGWF 1051
Cdd:cd00174    10 AQDDDELSFKKGDIITVLEKDDDGWWEGELN----GGREGLF 47

C-terminal Src Homology 3 domain of Nebulette and LIM-nebulette (or Lasp2); Nebulette is a cardiac-specific protein that localizes to the Z-disc. It interacts with tropomyosin and is important in stabilizing actin thin filaments in cardiac muscles. Polymorphisms in the nebulette gene are associated with dilated cardiomyopathy, with some mutations resulting in severe heart failure. Nebulette is a 107kD protein that contains an N-terminal acidic region, multiple nebulin repeats, and a C-terminal SH3 domain. LIM-nebulette, also called Lasp2 (LIM and SH3 domain protein 2), is an alternatively spliced variant of nebulette. Although it shares a gene with nebulette, Lasp2 is not transcribed from a muscle-specific promoter, giving rise to its multiple tissue expression pattern with highest amounts in the brain. It can crosslink actin filaments and it affects cell spreading. Lasp2 is a 34kD protein containing an N-terminal LIM domain, three nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212868 [Multi-domain] Cd Length: 58 Bit Score: 46.92 E-value: 1.54e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEV--AGVTGLFPTNYVKM 1127
Cdd:cd11935     5 AMYDYSAQDEDEVSFRDGDYIVNVQPIDEGWMYGTVqrTGRTGMLPANYIEF 56

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212700 [Multi-domain] Cd Length: 53 Bit Score: 46.49 E-value: 1.62e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQEN-WWYGELKEKRGWFPCSHVS 904
Cdd:cd11766     1 PAVVKFNYEAQREDELSLRKGDRVLVLEKSSDgWWRGECNGQVGWFPSNYVT 52

Src Homology 3 domain of Tec (Tyrosine kinase expressed in hepatocellular carcinoma); Tec is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. It is more widely-expressed than other Tec subfamily kinases. Tec is found in endothelial cells, both B- and T-cells, and a variety of myeloid cells including mast cells, erythroid cells, platelets, macrophages and neutrophils. Tec is a key component of T-cell receptor (TCR) signaling, and is important in TCR-stimulated proliferation, IL-2 production and phospholipase C-gamma1 activation. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212838 [Multi-domain] Cd Length: 56 Bit Score: 46.73 E-value: 1.68e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKG-EVAGVTGLFPTNYV 1125
Cdd:cd11905     3 VVAMYDFQPTEPHDLRLETGEEYVILEKNDVHWWKArDKYGKEGYIPSNYV 53

C-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domains (SH3c) of the related proteins, GRB2 and GRAP2, have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212884 Cd Length: 53 Bit Score: 46.33 E-value: 1.75e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11951     4 AQYDFSAEDPSQLSFRRGDIIEVLDCpDPNWWRGRISGRVGFFPRNYVHP 53

Src homology 3 domain of Phospholipase C (PLC) gamma; PLC catalyzes the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG) in response to various receptors. Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma catalyzes this reaction in tyrosine kinase-dependent signaling pathways. It is activated and recruited to its substrate at the membrane. Vertebrates contain two forms of PLCgamma, PLCgamma1, which is widely expressed, and PLCgamma2, which is primarily found in haematopoietic cells. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212759 [Multi-domain] Cd Length: 54 Bit Score: 46.56 E-value: 1.84e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQ-VDEstvRETGWLYGSYSG-NRGWFPESYAE 804
Cdd:cd11825     1 TVKALYDYRAQRPDELSFCKHAIITnVEK---EDGGWWRGDYGGkKQKWFPANYVE 53

C2 domain found in fungal Ingression 1 (Inn1) proteins; Saccharomyces cerevisiae Inn1 associates with the contractile actomyosin ring at the end of mitosis and is needed for cytokinesis. The C2 domain of Inn1, located at the N-terminus, is required for ingression of the plasma membrane. The C-terminus is relatively unstructured and contains eight PXXP motifs that are thought to mediate interaction of Inn1 with other proteins with SH3 domains in the cytokinesis proteins Hof1 (an F-BAR protein) and Cyk3 (whose overexpression can restore primary septum formation in Inn1Delta cells) as well as recruiting Inn1 to the bud-neck by binding to Cyk3. Inn1 and Cyk3 appear to cooperate in activating chitin synthase Chs2 for primary septum formation, which allows coordination of actomyosin ring contraction with ingression of the cleavage furrow. It is thought that the C2 domain of Inn1 helps to preserve the link between the actomyosin ring and the plasma membrane, contributing both to membrane ingression, as well as to stability of the contracting ring. Additionally, Inn1 might induce curvature of the plasma membrane adjacent to the contracting ring, thereby promoting ingression of the membrane. It has been shown that the C2 domain of human synaptotagmin induces curvature in target membranes and thereby contributes to fusion of these membranes with synaptic vesicles. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 176063 [Multi-domain] Cd Length: 118 Bit Score: 48.40 E-value: 1.84e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELkpckPN----GKSNPYCELTMGAQcyTSRHQPD---TLNPKWSFNCQFFIKDLYQDVLCLTVFErDQ 1583
Cdd:cd08681     1 GTLVVVVLKARNL----PNkrklDKQDPYCVLRIGGV--TKKTKTDfrgGQHPEWDEELRFEITEDKKPILKVAVFD-DD 73

                          90
                  ....*....|..
gi 688602146 1584 FSPDDFLGRTEV 1595
Cdd:cd08681    74 KRKPDLIGDTEV 85

helix-rich Mycoplasma protein; Members of this family occur strictly within a subset of Mycoplasma species. Members average 750 amino acids in length, including signal peptide. Sequences are predicted (Jpred 3) to be almost entirely alpha-helical. These sequences show strong periodicity (consistent with long alpha helical structures) and low complexity rich in D,E,N,Q, and K. Genes encoding these proteins are often found in tandem. The function is unknown.

Pssm-ID: 275316 [Multi-domain] Cd Length: 745 Bit Score: 52.72 E-value: 1.86e-06

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   460 QKEKEQND--IQRLKDRKRSLEIELEAVGNK-----HKQISSQLRDAKSKRQGQWAEL----ELINQRRDVcITDI---- 524
Cdd:TIGR04523  273 QKELEQNNkkIKELEKQLNQLKSEISDLNNQkeqdwNKELKSELKNQEKKLEEIQNQIsqnnKIISQLNEQ-ISQLkkel 351

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   525 -------NSLQLQFDEMQRQLNQLGPEKQRLADRLVHFTQNISS--PLINDVKQSVCEKDRSCRKLKEQLDVLERETTAK 595
Cdd:TIGR04523  352 tnsesenSEKQRELEEKQNEIEKLKKENQSYKQEIKNLESQINDleSKIQNQEKLNQQKDEQIKKLQQEKELLEKEIERL 431

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....
gi 688602146   596 LSQMEQYNKEIKELRQKQSQQQDVLEQLRRVRSD---KLKELQR 636
Cdd:TIGR04523  432 KETIIKNNSEIKDLTNQDSVKELIIKNLDNTRESletQLKVLSR 475

C2 domain fifth repeat in Ferlin; Ferlins are involved in vesicle fusion events. Ferlins and other proteins, such as Synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1). Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the fifth C2 repeat, C2E, and has a type-II topology.

Pssm-ID: 176002 [Multi-domain] Cd Length: 124 Bit Score: 48.70 E-value: 1.92e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1515 VTVLEATELKPCKPNGKSNPYCELTMGAQCYTSR--HQPDTLNPKwsFNCQFFIK-DLYQD-VLCLTVFERDQFSPDDFL 1590
Cdd:cd04037     4 VYVVRARNLQPKDPNGKSDPYLKIKLGKKKINDRdnYIPNTLNPV--FGKMFELEaTLPGNsILKISVMDYDLLGSDDLI 81


                  ....*
gi 688602146 1591 GRTEV 1595
Cdd:cd04037    82 GETVI 86

Src homology 3 domain of ephexin-1-like SH3 domain containing Rho guanine nucleotide exchange factors; Members of this family contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and C-terminal SH3 domains. They include the Rho guanine nucleotide exchange factors ARHGEF5, ARHGEF16, ARHGEF19, ARHGEF26, ARHGEF27 (also called ephexin-1), and similar proteins, and are also called ephexins because they interact directly with ephrin A receptors. GEFs interact with Rho GTPases via their DH domains to catalyze nucleotide exchange by stabilizing the nucleotide-free GTPase intermediate. They play important roles in neuronal development. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212727 [Multi-domain] Cd Length: 55 Bit Score: 46.56 E-value: 1.93e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVA--GVTGLFPTNYV 1125
Cdd:cd11793     1 QVQCVHAYTAQQPDELTLEEGDVVNVLRKMPDGWYEGERLrdGERGWFPSSYT 53

Src homology 3 domain of Protein arginine N-methyltransferase 2; PRMT2, also called HRMT1L1, belongs to the arginine methyltransferase protein family. It functions as a coactivator to both estrogen receptor alpha (ER-alpha) and androgen receptor (AR), presumably through arginine methylation. The ER-alpha transcription factor is involved in cell proliferation, differentiation, morphogenesis, and apoptosis, and is also implicated in the development and progression of breast cancer. PRMT2 and its variants are upregulated in breast cancer cells and may be involved in modulating the ER-alpha signaling pathway during formation of breast cancer. PRMT2 also plays a role in regulating the function of E2F transcription factors, which are critical cell cycle regulators, by binding to the retinoblastoma gene product (RB). It contains an N-terminal SH3 domain and an AdoMet binding domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212740 [Multi-domain] Cd Length: 53 Bit Score: 46.23 E-value: 2.09e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHVS 904
Cdd:cd11806     3 VAIADFVATDDSQLSFESGDKLLVLRKpSVDWWWAEHNGCCGYIPASHLH 52

Src homology 3 domain of an unknown subfamily of proteins with similarity to Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212932 [Multi-domain] Cd Length: 56 Bit Score: 46.47 E-value: 2.19e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVL-NKDNPDWWKG-EVAGVTGLFPTNYV 1125
Cdd:cd11999     3 RVRAVYDYTGQEPDELSFKAGEELLKVeDEDEQGWCKGvTDGGAVGLYPANYV 55

Src homology 3 domain of ARHGEF9-like Rho guanine nucleotide exchange factors; Members of this family contain a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. They include the Rho guanine nucleotide exchange factors ARHGEF9, ASEF (also called ARHGEF4), ASEF2, and similar proteins. GEFs activate small GTPases by exchanging bound GDP for free GTP. ARHGEF9 specifically activates Cdc42, while both ASEF and ASEF2 can activate Rac1 and Cdc42. ARHGEF9 is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. ASEF plays a role in angiogenesis and cell migration. ASEF2 is important in cell migration and adhesion dynamics. ASEF exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli), leading to the activation of Rac1 or Cdc42. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212762 [Multi-domain] Cd Length: 53 Bit Score: 46.22 E-value: 2.37e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11828     2 AEALWDHVTMDPEELGFKAGDVIEVLDMSDkDWWWGSIRDEEGWFPASFVRL 53

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor 2; ASEF2, also called Spermatogenesis-associated protein 13 (SPATA13), is a GEF that localizes with actin at the leading edge of cells and is important in cell migration and adhesion dynamics. GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF2 can activate both Rac 1 and Cdc42, but only Rac1 activation is necessary for increased cell migration and adhesion turnover. Together with APC (adenomatous polyposis coli) and Neurabin2, a scaffold protein that binds F-actin, it is involved in regulating HGF-induced cell migration. ASEF2 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212907 Cd Length: 54 Bit Score: 46.21 E-value: 2.46e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11974     5 ALWDHVTMDDQELAFKAGDVIRVLEASNKDWWWGRNEDREAWFPASFVRL 54

Src homology 3 domain of Growth Arrest Specific protein 7; GAS7 is mainly expressed in the brain and is required for neurite outgrowth. It may also play a role in the protection and migration of embryonic stem cells. Treatment-related acute myeloid leukemia (AML) has been reported resulting from mixed-lineage leukemia (MLL)-GAS7 translocations as a complication of primary cancer treatment. GAS7 contains an N-terminal SH3 domain, followed by a WW domain, and a central F-BAR domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212763 [Multi-domain] Cd Length: 52 Bit Score: 45.97 E-value: 2.51e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1073 LCQviAMYDYKAANKDE-MSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11829     1 LCR--TLYAFTGEQHQQgLSFEAGELIRVLQAPDGGWWEGEKDGLRGWFPASYV 52

Src Homology 3 domain of Bruton's tyrosine kinase; BTK is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain with proline-rich and zinc-binding regions. Btk is expressed in B-cells, and a variety of myeloid cells including mast cells, platelets, neutrophils, and dendrictic cells. It interacts with a variety of partners, from cytosolic proteins to nuclear transcription factors, suggesting a diversity of functions. Stimulation of a diverse array of cell surface receptors, including antigen engagement of the B-cell receptor (BCR), leads to PH-mediated membrane translocation of Btk and subsequent phosphorylation by Src kinase and activation. Btk plays an important role in the life cycle of B-cells including their development, differentiation, proliferation, survival, and apoptosis. Mutations in Btk cause the primary immunodeficiency disease, X-linked agammaglobulinaemia (XLA) in humans. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212839 [Multi-domain] Cd Length: 55 Bit Score: 45.97 E-value: 2.53e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVA-GVTGLFPTNYV 1125
Cdd:cd11906     3 VVALYDYTPMNAQDLQLRKGEEYVILEESNLPWWRARDKnGREGYIPSNYV 53

Second C-terminal Src homology 3 domain of Rho guanine nucleotide exchange factor 37; ARHGEF37 contains a RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. Its specific function is unknown. Its domain architecture is similar to the C-terminal half of DNMBP or Tuba, a cdc42-specific GEF that provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics, and plays an important role in regulating cell junction configuration. GEFs activate small GTPases by exchanging bound GDP for free GTP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212874 Cd Length: 57 Bit Score: 46.06 E-value: 2.53e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVL----NKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11941     1 QVVAAYPFTARSKHEVSLQAGQPVTVLephdKKGSPEWSLVEVNGQRGYVPSSYL 55

Src homology 3 domain of Lyn Protein Tyrosine Kinase; Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212937 [Multi-domain] Cd Length: 56 Bit Score: 46.14 E-value: 2.75e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGEWW--RGCIGDQTGLFPSNYV 982
Cdd:cd12004     3 VALYPYDGIHEDDLSFKKGEKLKVIEEHGEWWkaRSLTTKKEGFIPSNYV 52

Src homology 3 domain of Src Protein Tyrosine Kinase; Src (or c-Src) is a cytoplasmic (or non-receptor) PTK and is the vertebrate homolog of the oncogenic protein (v-Src) from Rous sarcoma virus. Together with other Src subfamily proteins, it is involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. Src also play a role in regulating cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Elevated levels of Src kinase activity have been reported in a variety of human cancers. Several inhibitors of Src have been developed as anti-cancer drugs. Src is also implicated in acute inflammatory responses and osteoclast function. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212941 [Multi-domain] Cd Length: 56 Bit Score: 45.87 E-value: 2.77e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  934 YVALYTYESPESGDLTF-SAEDVVLVTEKEGEWW--RGCIGDQTGLFPSNYVKP 984
Cdd:cd12008     2 FVALYDYESRTETDLSFkKGERLQIVNNTEGDWWlaHSLTTGQTGYIPSNYVAP 55

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor 2; ASEF2, also called Spermatogenesis-associated protein 13 (SPATA13), is a GEF that localizes with actin at the leading edge of cells and is important in cell migration and adhesion dynamics. GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF2 can activate both Rac 1 and Cdc42, but only Rac1 activation is necessary for increased cell migration and adhesion turnover. Together with APC (adenomatous polyposis coli) and Neurabin2, a scaffold protein that binds F-actin, it is involved in regulating HGF-induced cell migration. ASEF2 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212907 Cd Length: 54 Bit Score: 45.83 E-value: 3.06e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLE-KQENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11974     3 AEALWDHVTMDDQELAFKAGDVIRVLEaSNKDWWWGRNEDREAWFPASFVRL 54

Pleckstrin homology domain-containing family G member 7 pleckstrin homology (PH) domain; PLEKHG7 has a RhoGEF DH/double-homology domain in tandem with a PH domain which is involved in phospholipid binding. PLEKHG7 is proposed to functions as a guanine nucleotide exchange factor (GEF) and is involved in the regulation of Rho protein signal transduction. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 270065 Cd Length: 128 Bit Score: 48.04 E-value: 3.27e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1378 KLLHSGKLHKTKSSK--ELWALLFNDFLLLTYT----SKQFSS-------SPDKLFNPNSNTQYKMYKTPVFLNEVLVK- 1443
Cdd:cd13245     1 QLLHEGPLTLIESGKtlDVYLFLFDDMLLITKMkknlKKKKSSdsensmpSLELTPLIKEGGSYTVYKQPIPLDRLCLHd 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146 1444 -MPSDPSSDD--PVFHISHIDR------VYTLKTDTINERTTWVQKIK 1482
Cdd:cd13245    81 vDPNEATANGlkHAFVLVHLNRyqqvigVYTLQASSENTKQTWMSKLR 128

First Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212861 Cd Length: 54 Bit Score: 45.68 E-value: 3.37e-06

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11928     5 ALYSYEGKEPGDLKFNKGDIIILRRKVDEnWYHGELNGCHGFLPASYIQ 53

Src homology 3 domain of Blk Protein Tyrosine Kinase; Blk is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. It is expressed specifically in B-cells and is involved in pre-BCR (B-cell receptor) signaling. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212942 [Multi-domain] Cd Length: 54 Bit Score: 45.58 E-value: 3.53e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGEWW--RGCIGDQTGLFPSNYVKP 984
Cdd:cd12009     2 VIAQYDFVPSNERDLQLKKGEKLQVLKSDGEWWlaKSLTTGKEGYIPSNYVAR 54

Src homology 3 domain of Cortactin; Cortactin was originally identified as a substrate of Src kinase. It is an actin regulatory protein that binds to the Arp2/3 complex and stabilizes branched actin filaments. It is involved in cellular processes that affect cell motility, adhesion, migration, endocytosis, and invasion. It is expressed ubiquitously except in hematopoietic cells, where the homolog hematopoietic lineage cell-specific 1 (HS1) is expressed instead. Cortactin contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region interacts with the Arp2/3 complex and F-actin, and is crucial in regulating branched actin assembly. Cortactin also serves as a scaffold and provides a bridge to the actin cytoskeleton for membrane trafficking and signaling proteins that bind to its SH3 domain. Binding partners for the SH3 domain of cortactin include dynamin2, N-WASp, MIM, FGD1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212892 [Multi-domain] Cd Length: 53 Bit Score: 45.49 E-value: 3.62e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11959     2 AVALYDYQAADDDEISFDPDDIITNIEMiDEGWWRGVCRGKYGLFPANYVEL 53

Src Homology 3 domain of alpha-Pak Interactive eXchange factor; Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6) or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212993 Cd Length: 58 Bit Score: 45.76 E-value: 3.64e-06

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTE-KEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd12060     6 ARFNFKQTNEDELSVCKGDIIYVTRvEEGGWWEGTLNGKTGWFPSNYVR 54

Fifth Src homology 3 domain (or SH3E) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212928 [Multi-domain] Cd Length: 54 Bit Score: 45.33 E-value: 4.09e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11995     2 QVIGMYDYTAQNDDELAFSKGQIINVLNKEDpDWWKGELNGQVGLFPSNYVKL 54

Src homology 3 domain of Lck Protein Tyrosine Kinase; Lck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cells and natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212938 [Multi-domain] Cd Length: 54 Bit Score: 45.59 E-value: 4.14e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGEWWRG--CIGDQTGLFPSNYV 982
Cdd:cd12005     3 VALYSYEPSHDGDLGFEKGEKLRILEQSGEWWKAqsLTTGQEGFIPFNFV 52

C2 domain in Protein Kinase C (PKC) alpha and gamma; A single C2 domain is found in PKC alpha and gamma. The PKC family of serine/threonine kinases regulates apoptosis, proliferation, migration, motility, chemo-resistance, and differentiation. There are 3 groups: group 1(alpha, betaI, beta II, gamma) which require phospholipids and calcium, group 2 (delta, epsilon, theta, eta) which do not require calcium for activation, and group 3 (xi, iota/lambda) which are atypical and can be activated in the absence of diacylglycerol and calcium. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have a type-I topology.

Pssm-ID: 175992 [Multi-domain] Cd Length: 131 Bit Score: 47.64 E-value: 4.23e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKPCKPNGKSNPYCELTMgaqcytsrhQPD--------------TLNPKWsfNCQFFIKDLYQDV--- 1573
Cdd:cd04026    13 NKLTVEVREAKNLIPMDPNGLSDPYVKLKL---------IPDpknetkqktktikkTLNPVW--NETFTFDLKPADKdrr 81

                          90       100       110
                  ....*....|....*....|....*....|.
gi 688602146 1574 LCLTVFERDQFSPDDFLGRTEVPVATIKKDQ 1604
Cdd:cd04026    82 LSIEVWDWDRTTRNDFMGSLSFGVSELIKMP 112

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212790 [Multi-domain] Cd Length: 53 Bit Score: 45.32 E-value: 4.23e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 688602146  751 TYRALYPFTARNSDELTLEADcfiqvDESTVRET---GWLYGSYSGNRGWFPESYAER 805
Cdd:cd11856     1 SYVAIADYEAQGDDEISLQEG-----EVVEVLEKndsGWWYVRKGDKEGWVPASYLEP 53

C2 domain first repeat; fungal group; C2 domains were first identified in Protein Kinase C (PKC). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 176006 [Multi-domain] Cd Length: 111 Bit Score: 47.26 E-value: 4.28e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKPCKPN-GKSNPYCELTM---GAQCYTSRHQPDTLNPKWsfNCQFFIKDLYQDV-----LCLTVFER 1581
Cdd:cd04041     1 GVLVVTIHRATDLPKADFGtGSSDPYVTASFakfGKPLYSTRIIRKDLNPVW--EETWFVLVTPDEVkagerLSCRLWDS 78

                          90       100
                  ....*....|....*....|..
gi 688602146 1582 DQFSPDDFLGRTEVPVATIKKD 1603
Cdd:cd04041    79 DRFTADDRLGRVEIDLKELIED 100

First Src homology 3 domain (or SH3A) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212920 [Multi-domain] Cd Length: 55 Bit Score: 45.38 E-value: 4.36e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDN--PDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11987     4 ALYPFEARSHDEITIQPGDIVMVDESQTgePGWLGGELKGKTGWFPANYAE 54

Src homology 3 domain of ephexin-1-like SH3 domain containing Rho guanine nucleotide exchange factors; Members of this family contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and C-terminal SH3 domains. They include the Rho guanine nucleotide exchange factors ARHGEF5, ARHGEF16, ARHGEF19, ARHGEF26, ARHGEF27 (also called ephexin-1), and similar proteins, and are also called ephexins because they interact directly with ephrin A receptors. GEFs interact with Rho GTPases via their DH domains to catalyze nucleotide exchange by stabilizing the nucleotide-free GTPase intermediate. They play important roles in neuronal development. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212727 [Multi-domain] Cd Length: 55 Bit Score: 45.40 E-value: 4.41e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  754 ALYPFTARNSDELTLEADCFIQVdestVRET--GWLYGS--YSGNRGWFPESYAE 804
Cdd:cd11793     4 CVHAYTAQQPDELTLEEGDVVNV----LRKMpdGWYEGErlRDGERGWFPSSYTE 54

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1; SKAP1, also called SKAP55 (Src kinase-associated protein of 55kDa), is an immune cell-specific adaptor protein that plays an important role in T-cell adhesion, migration, and integrin clustering. It is expressed exclusively in T-lymphocytes, mast cells, and macrophages. Binding partners include ADAP (adhesion and degranulation-promoting adaptor protein), Fyn, Riam, RapL, and RasGRP. It contains a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212977 Cd Length: 53 Bit Score: 45.23 E-value: 4.66e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNP--DWWKGEVAGVTGLFPTNYV 1125
Cdd:cd12044     4 GLWDCFGDNPDELSFQRGDLIYILSKEYNmyGWWVGELNGIVGIVPKDYL 53

Second C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212894 [Multi-domain] Cd Length: 53 Bit Score: 45.21 E-value: 4.70e-06

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTE-KEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11961     4 ALYDYDAAEDNELSFFENDKIINIEfVDDDWWLGECHGSRGLFPSNYVE 52

Src Homology 3 domain of Small G protein Signaling Modulator 3; SGSM3 is also called Merlin-associated protein (MAP), RUN and SH3 domain-containing protein (RUSC3), RUN and TBC1 domain-containing protein 3 (RUTBC3), Rab GTPase-activating protein 5 (RabGAP5), or Rab GAP-like protein (RabGAPLP). It is expressed ubiquitously and functions as a regulator of small G protein RAP- and RAB-mediated neuronal signaling. It is involved in modulating NGF-mediated neurite outgrowth and differentiation. It also interacts with the tumor suppressor merlin and may play a role in the merlin-associated suppression of cell growth. SGSM3 contains TBC, SH3, and RUN domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212747 Cd Length: 53 Bit Score: 45.18 E-value: 4.74e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11813     4 ALLDFERHDDDELGFRKNDIITIISQKDEHCWVGELNGLRGWFPAKFVEL 53

Third Src Homology 3 domain of SH3 domain containing ring finger 1 (SH3RF1), SH3RF3, and similar domains; SH3RF1 (or POSH) and SH3RF3 (or POSH2) are scaffold proteins that function as E3 ubiquitin-protein ligases. They contain an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle of SH3RF1 and SH3RF3, and similar domains. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212717 [Multi-domain] Cd Length: 55 Bit Score: 45.08 E-value: 5.05e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEK--EGeWWRGC--IGDQTGLFPSNYVKP 984
Cdd:cd11783     2 YVALYPYKPQKPDELELRKGEMYTVTEKcqDG-WFKGTslRTGQSGVFPGNYVQP 55

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 394975 [Multi-domain] Cd Length: 47 Bit Score: 44.89 E-value: 5.15e-06

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*...
gi 688602146   753 RALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSY-SGNRGWFP 799
Cdd:pfam00018    1 VALYDYTAQEPDELSFKKGDIIIVLEKS--EDGWWKGRNkGGKEGLIP 46

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 275388 [Multi-domain] Cd Length: 92 Bit Score: 46.38 E-value: 5.16e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1381 HSGKLHKT-----KSSKELWALLFNDFLLLTYTSKQFSSSPdklfnpnsntqykmyKTPVFLNEVLVKMPSDPSSDDPVF 1455
Cdd:cd00821     1 KEGYLLKRgggglKSWKKRWFVLFEGVLLYYKSKKDSSYKP---------------KGSIPLSGILEVEEVSPKERPHCF 65

                          90       100
                  ....*....|....*....|....*..
gi 688602146 1456 HISH-IDRVYTLKTDTINERTTWVQKI 1481
Cdd:cd00821    66 ELVTpDGRTYYLQADSEEERQEWLKAL 92

Src Homology 3 domain of TXK, also called Resting lymphocyte kinase (Rlk); TXK is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal cysteine-rich region. Rlk is expressed in T-cells and mast cell lines, and is a key component of T-cell receptor (TCR) signaling. It is important in TCR-stimulated proliferation, IL-2 production and phospholipase C-gamma1 activation. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212840 [Multi-domain] Cd Length: 55 Bit Score: 45.33 E-value: 5.22e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKG-EVAGVTGLFPTNYV 1125
Cdd:cd11907     2 QVKALYDFLPREPSNLALKRAEEYLILEQYDPHWWKArDRYGNEGLIPSNYV 53

Src homology 3 domain of Lyn Protein Tyrosine Kinase; Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212937 [Multi-domain] Cd Length: 56 Bit Score: 44.98 E-value: 5.58e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLnKDNPDWWKGE--VAGVTGLFPTNYV 1125
Cdd:cd12004     2 VVALYPYDGIHEDDLSFKKGEKLKVI-EEHGEWWKARslTTKKEGFIPSNYV 52

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212700 [Multi-domain] Cd Length: 53 Bit Score: 44.95 E-value: 5.74e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNRGWFPESYAER 805
Cdd:cd11766     1 PAVVKFNYEAQREDELSLRKGDRVLVLEKS--SDGWWRGECNGQVGWFPSNYVTE 53

Src Homology 3 domain of Class A and B Dedicator of Cytokinesis proteins; DOCK proteins are atypical guanine nucleotide exchange factors (GEFs) that lack the conventional Dbl homology (DH) domain. They are divided into four classes (A-D) based on sequence similarity and domain architecture: class A includes Dock1, 2 and 5; class B includes Dock3 and 4; class C includes Dock6, 7, and 8; and class D includes Dock9, 10 and 11. All DOCKs contain two homology domains: the DHR-1 (Dock homology region-1), also called CZH1 (CED-5, Dock180, and MBC-zizimin homology 1), and DHR-2 (also called CZH2 or Docker). The DHR-1 domain binds phosphatidylinositol-3,4,5-triphosphate while DHR-2 contains the catalytic activity for Rac and/or Cdc42. This subfamily includes only Class A and B DOCKs, which also contain an SH3 domain at the N-terminal region and a PxxP motif at the C-terminus. Class A/B DOCKs are mostly specific GEFs for Rac, except Dock4 which activates the Ras family GTPase Rap1, probably indirectly through interaction with Rap regulatory proteins. The SH3 domain of class A/B DOCKs have been shown to bind Elmo, a scaffold protein that promotes GEF activity of DOCKs by releasing DHR-2 autoinhibition by the intramolecular SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212805 [Multi-domain] Cd Length: 56 Bit Score: 44.88 E-value: 5.77e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGEWWRGCI---GDQTGLFPSNYVKPK 985
Cdd:cd11872     3 VAIYNFQGDGEHQLSLQVGDTVQILEECEGWYRGFSlrnKSLKGIFPKSYVHIK 56

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member 4; CASS4, also called HEPL (HEF1-EFS-p130Cas-like), localizes to focal adhesions and plays a role in regulating FAK activity, focal adhesion integrity, and cell spreading. It is most abundant in blood cells and lung tissue, and is also found in high levels in leukemia and ovarian cell lines. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212933 Cd Length: 57 Bit Score: 45.26 E-value: 6.02e-06

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPD---WWKGEVAGVTGLFPTN 1123
Cdd:cd12000     5 ALYDNKADCSDELAFRRGDILTVLEQNVPGsegWWKCLLHGRQGLAPAN 53

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213017 [Multi-domain] Cd Length: 57 Bit Score: 44.80 E-value: 6.45e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLN-KD---NPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12141     4 AVYTFKARSPNELSVSANQRVRILEfSDltgNKEWWLAEANGQKGYVPSNYIR 56

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase 3; GRAF3 is also called Rho GTPase activating protein 42 (ARHGAP42) or ARHGAP10-like. Though its function has not been characterized, it may be a GAP with activity towards RhoA and Cdc42, based on its similarity to GRAF and GRAF2. It contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212999 Cd Length: 55 Bit Score: 45.05 E-value: 6.62e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLIT-VLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd12066     1 QAKAMYSCKAEHSHELSFPQGAIFSnVYPSVEPGWLKATYEGKTGLVPENYV 52

C-terminal (or second) Src homology 3 domain of VAV2 protein; VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212910 [Multi-domain] Cd Length: 58 Bit Score: 45.00 E-value: 6.65e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPD--WWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11977     4 VARYNFAARDMRELSLREGDVVRIYSRIGGDqgWWKGETNGRIGWFPSTYVE 55

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1 and similar proteins; This subfamily is composed of SKAP1, SKAP2, and similar proteins. SKAP1 and SKAP2 are immune cell-specific adaptor proteins that play roles in T- and B-cell adhesion, respectively, and are thus important in the migration of T- and B-cells to sites of inflammation and for movement during T-cell conjugation with antigen-presenting cells. Both SKAP1 and SKAP2 bind to ADAP (adhesion and degranulation-promoting adaptor protein), among many other binding partners. They contain a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212800 Cd Length: 53 Bit Score: 44.73 E-value: 7.14e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNK--DNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11866     4 GLWDCSGNEPDELSFKRGDLIYIISKeyDSFGWWVGELNGKVGLVPKDYL 53

C2 domain present in the Human neural precursor cell-expressed, developmentally down-regulated 4 (NEDD4) and NEDD4-like (NEDD4L/NEDD42); Nedd4 and Nedd4-2 are two of the nine members of the Human Nedd4 family. All vertebrates appear to have both Nedd4 and Nedd4-2 genes. They are thought to participate in the regulation of epithelial Na+ channel (ENaC) activity. They also have identical specificity for ubiquitin conjugating enzymes (E2). Nedd4 and Nedd4-2 are composed of a C2 domain, 2-4 WW domains, and a ubiquitin ligase Hect domain. Their WW domains can bind PPxY (PY) or LPSY motifs, and in vitro studies suggest that WW3 and WW4 of both proteins bind PY motifs in the key substrates, with WW3 generally exhibiting higher affinity. Most Nedd4 family members, especially Nedd4-2, also have multiple splice variants, which might play different roles in regulating their substrates. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 175999 [Multi-domain] Cd Length: 133 Bit Score: 46.96 E-value: 7.46e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1513 LLVTVLEATELKPCKPNGKSNPYCELTM----GAQCYTSRH---QPDTLNPKWsfNCQFFIK-DLYQDVLCLTVFERDQF 1584
Cdd:cd04033     2 LRVKVLAGIDLAKKDIFGASDPYVKISLydpdGNGEIDSVQtktIKKTLNPKW--NEEFFFRvNPREHRLLFEVFDENRL 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1585 SPDDFLGRTEVPVATIKKDQDGK--GPLVRRLLLHevPTGE-VKVRLDLQLY 1633
Cdd:cd04033    80 TRDDFLGQVEVPLNNLPTETPGNerRYTFKDYLLR--PRSSkSRVKGHLRLY 129

Src homology 3 domain of Ubiquitin-associated and SH3 domain-containing protein B; UBASH3B, also called Suppressor of T cell receptor Signaling (STS)-1 or T cell Ubiquitin LigAnd (TULA)-2 is an active phosphatase that is expressed ubiquitously. The phosphatase activity of UBASH3B is essential for its roles in the suppression of TCR signaling and the regulation of EGFR. It also interacts with Syk and functions as a negative regulator of platelet glycoprotein VI signaling. TULA proteins contain an N-terminal UBA domain, a central SH3 domain, and a C-terminal histidine phosphatase domain. They bind c-Cbl through the SH3 domain and to ubiquitin via UBA. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212869 Cd Length: 62 Bit Score: 45.03 E-value: 7.54e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  751 TYRALYPFTARNSDELTLEADCFI---QVDESTVREtGWLYGSY--SGNRGWFPESY 802
Cdd:cd11936     3 TLQVIYPYTPQNDDELELVPGDYIfmsPMEQTSTSE-GWIYGTSltTGCSGLLPENY 58

Second Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the second SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212716 [Multi-domain] Cd Length: 53 Bit Score: 44.65 E-value: 7.55e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11782     1 EARAKYNFNADTGVELSFRKGDVITLTRRvDENWYEGRIGGRQGIFPVSYVQV 53

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 2; SKAP2, also called SKAP55-Related (SKAP55R) or SKAP55 homolog (SKAP-HOM or SKAP55-HOM), is an immune cell-specific adaptor protein that plays an important role in adhesion and migration of B-cells and macrophages. Binding partners include ADAP (adhesion and degranulation-promoting adaptor protein), YopH, SHPS1, and HPK1. SKAP2 has also been identified as a substrate for lymphoid-specific tyrosine phosphatase (Lyp), which has been implicated in a wide variety of autoimmune diseases. It contains a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. Like SKAP1, SKAP2 is expected to bind primarily to a proline-rich region of ADAP through its SH3 domain; its degradation may be regulated by ADAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212978 Cd Length: 53 Bit Score: 44.51 E-value: 7.69e-06

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1079 MYDYKAANKDEMSFQKGQLITVLNK--DNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd12045     5 LWDCTGDQPDELSFKRGDTIYILSKeyNRFGWWVGEMKGTIGLVPKAYI 53

First Src homology 3 domain (or SH3A) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The first SH3 domain (or SH3A) of ITSN2 is expected to bind many protein partners, similar to ITSN1 which has been shown to bind Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212921 [Multi-domain] Cd Length: 57 Bit Score: 44.86 E-value: 7.80e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEK---EGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11988     4 YRALYPFEARNHDEMSFNAGDIIQVDEKtvgEPGWLYGSFQGNFGWFPCNYVE 56

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor; ASEF, also called ARHGEF4, exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli). GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF can activate Rac1 or Cdc42. Truncated ASEF, which is found in colorectal cancers, is constitutively active and has been shown to promote angiogenesis and cancer cell migration. ASEF contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212906 [Multi-domain] Cd Length: 73 Bit Score: 45.39 E-value: 7.85e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11973    22 ALWDHVTMDDQELGFKAGDVIEVMDATNKEWWWGRVLDSEGWFPASFVRL 71

Src homology 3 domain of the Rho guanine nucleotide exchange factor ARHGEF9; ARHGEF9, also called PEM2 or collybistin, selectively activates Cdc42 by exchanging bound GDP for free GTP. It is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. Mutations in the ARHGEF9 gene cause X-linked mental retardation with associated features like seizures, hyper-anxiety, aggressive behavior, and sensory hyperarousal. ARHGEF9 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212908 Cd Length: 62 Bit Score: 44.70 E-value: 8.49e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11975     9 AVWDHVTMANRELAFKAGDVIKVLDASNKDWWWGQIDDEEGWFPASFVRL 58

Second Src Homology 3 domain of SH3 domain containing ring finger proteins; This model represents the second SH3 domain of SH3RF1 (or POSH), SH3RF2 (or POSHER), SH3RF3 (POSH2), and similar domains. Members of this family are scaffold proteins that function as E3 ubiquitin-protein ligases. They all contain an N-terminal RING finger domain and multiple SH3 domains; SH3RF1 and SH3RF3 have four SH3 domains while SH3RF2 has three. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3RF2 acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212721 [Multi-domain] Cd Length: 53 Bit Score: 44.63 E-value: 8.59e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1075 QVIAMYDYKAANKDE---MSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNY 1124
Cdd:cd11787     1 QCKALYDFEMKDEDEkdcLTFKKGDVITVIRRVDENWAEGRLGDKIGIFPISF 53

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar proteins; This subfamily is composed of Rho GTPase activating proteins (GAPs) with similarity to GRAF. Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. Although vertebrates harbor four Rho GAPs in the GRAF subfamily including GRAF, GRAF2, GRAF3, and Oligophrenin-1 (OPHN1), only three are included in this model. OPHN1 contains the BAR, PH and GAP domains, but not the C-terminal SH3 domain. GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. GRAF influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase. GRAF2 regulates caspase-activated p21-activated protein kinase-2. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212815 [Multi-domain] Cd Length: 54 Bit Score: 44.59 E-value: 8.63e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  935 VALYTYESPESGDLTFSAEDV---VLVTEKEGeWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11882     3 RALYACKAEDESELSFEPGQIitnVQPSDEPG-WLEGTLNGRTGLIPENYVEF 54

Second Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212708 [Multi-domain] Cd Length: 52 Bit Score: 44.38 E-value: 8.77e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDW-WKGEVAGVTGLFPTNYV 1125
Cdd:cd11774     1 QAKALYDYDKQTEEELSFNEGDTLDVYDDSDSDWiLVGFNGTQFGFVPANYI 52

Src homology 3 domain of Endophilin-A; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain three endophilin-A isoforms (A1, A2, and A3). Endophilin-A proteins are enriched in the brain and play multiple roles in receptor-mediated endocytosis. They tubulate membranes and regulate calcium influx into neurons to trigger the activation of the endocytic machinery. They are also involved in the sorting of plasma membrane proteins, actin filament assembly, and the uncoating of clathrin-coated vesicles for fusion with endosomes. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212737 [Multi-domain] Cd Length: 55 Bit Score: 44.56 E-value: 8.89e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  934 YVALYTYESPESGDLTFSAEDVV-LVTEKEGEWWRGCIGDQTGLFPSNYV 982
Cdd:cd11803     3 CRALYDFEPENEGELGFKEGDIItLTNQIDENWYEGMVNGQSGFFPVNYV 52

First Src Homology 3 domain (SH3A) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CIN85; SH3A binds to internal proline-rich motifs within the proline-rich region. This intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. SH3A has also been shown to bind ubiquitin and to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic end of the cell adhesion protein CD2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212985 [Multi-domain] Cd Length: 53 Bit Score: 44.50 E-value: 8.95e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVL-VTEKEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd12052     1 EAIVEFDYKAQHEDELTITVGDIITkIKKDDGGWWEGEIKGRRGLFPDNFVR 52

Second Src homology 3 domain (or SH3B) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212771 [Multi-domain] Cd Length: 53 Bit Score: 44.28 E-value: 9.74e-06

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                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDEstvRETGWLYGSYS-GNRGWFPESY 802
Cdd:cd11837     1 TATALYPWRAKKENHLSFAKGDIITVLE---QQEMWWFGELEgGEEGWFPKSY 50

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

Pssm-ID: 214620 [Multi-domain] Cd Length: 56 Bit Score: 44.45 E-value: 9.82e-06

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|..
gi 688602146   1010 ATTPEQLSLTPGQLIVVLHKNSNSWWLGELqargKKRKKGWF 1051
Cdd:smart00326   13 AQDPDELSFKKGDIITVLEKSDDGWWKGRL----GRGKEGLF 50

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212757 [Multi-domain] Cd Length: 53 Bit Score: 44.26 E-value: 9.89e-06

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146 1010 ATTPEQLSLTPGQLIVVLHKNSNSWWLGELqaRGkkrKKGWFQSSNV 1056
Cdd:cd11823    10 ANREDELSLQPGDIIEVHEKQDDGWWLGEL--NG---KKGIFPATYV 51

Src homology 3 domain of SH3 protein interacting with Nck, 90 kDa (SPIN90); SPIN90 is also called NCK interacting protein with SH3 domain (NCKIPSD), Dia-interacting protein (DIP), 54 kDa vimentin-interacting protein (VIP54), or WASP-interacting SH3-domain protein (WISH). It is an F-actin binding protein that regulates actin polymerization and endocytosis. It associates with the Arp2/3 complex near actin filaments and determines filament localization at the leading edge of lamellipodia. SPIN90 is expressed in the early stages of neuronal differentiation and plays a role in regulating growth cone dynamics and neurite outgrowth. It also interacts with IRSp53 and regulates cell motility by playing a role in the formation of membrane protrusions. SPIN90 contains an N-terminal SH3 domain, a proline-rich domain, and a C-terminal VCA (verprolin-homology and cofilin-like acidic) domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212783 [Multi-domain] Cd Length: 53 Bit Score: 44.23 E-value: 1.02e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWK-GEVAGVTGLFPTNYVK 1126
Cdd:cd11849     4 ALYDFKSAEPNTLSFSEGETFLLLERSNAHWWLvTNHSGETGYVPANYVK 53

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing protein 2; ASAP2 is also called DDEF2 (Development and Differentiation Enhancing Factor 2), AMAP2, centaurin beta-3, or PAG3. It mediates the functions of Arf GTPases vial dual mechanisms: it exhibits GTPase activating protein (GAP) activity towards class I (Arf1) and II (Arf5) Arfs; and it binds class III Arfs (GTP-Arf6) stably without GAP activity. It binds paxillin and is implicated in Fcgamma receptor-mediated phagocytosis in macrophages and in cell migration. ASAP2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212899 Cd Length: 56 Bit Score: 44.18 E-value: 1.06e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAG---VTGLFPTNYV 1125
Cdd:cd11966     1 RVKALYNCVADNPDELTFSEGEIIIVDGEEDKEWWIGHIDGeptRRGAFPVSFV 54

Third Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212750 [Multi-domain] Cd Length: 51 Bit Score: 44.32 E-value: 1.07e-05

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                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEG-EWWRGCIGDQTGLFPSNYV 982
Cdd:cd11816     3 VARFDFEGEQEDELSFSEGDVITLKEYVGeEWAKGELNGKIGIFPLNFV 51

Second Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the second SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212949 Cd Length: 54 Bit Score: 44.37 E-value: 1.09e-05

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                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTVRetGWLYGSYSGNRGWFPESYAER 805
Cdd:cd12016     3 YITTQAYKAENEDEIGFETGVVVEVIQKNLD--GWWKIRYQGKEGWAPATYLKK 54

C2A domain first repeat present in Synaptotagmins 1, 5, 6, 9, and 10; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 1, a member of class 1 synaptotagmins, is located in the brain and endocranium and localized to the synaptic vesicles and secretory granules. It functions as a Ca2+ sensor for fast exocytosis as do synaptotagmins 5, 6, and 10. It is distinguished from the other synaptotagmins by having an N-glycosylated N-terminus. Synaptotagmins 5, 6, and 10, members of class 3 synaptotagmins, are located primarily in the brain and localized to the active zone and plasma membrane. They is distinguished from the other synaptotagmins by having disulfide bonds at its N-terminus. Synaptotagmin 6 also regulates the acrosome reaction, a unique Ca2+-regulated exocytosis, in sperm. Synaptotagmin 9, a class 5 synaptotagmins, is located in the brain and localized to the synaptic vesicles. It is thought to be a Ca2+-sensor for dense-core vesicle exocytosis. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

Pssm-ID: 176031 [Multi-domain] Cd Length: 124 Bit Score: 46.49 E-value: 1.10e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1507 NSGIGRLLVTVLEATELKPCKPNGKSNPYCELTM---GAQCYTSRHQPDTLNPkwSFNCQFFIKDLYQDV----LCLTVF 1579
Cdd:cd08385    12 DFQSNQLTVGIIQAADLPAMDMGGTSDPYVKVYLlpdKKKKFETKVHRKTLNP--VFNETFTFKVPYSELgnktLVFSVY 89

                          90       100
                  ....*....|....*....|.
gi 688602146 1580 ERDQFSPDDFLGRTEVPVATI 1600
Cdd:cd08385    90 DFDRFSKHDLIGEVRVPLLTV 110

Third Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. The third SH3 domain of Sla1p can bind ubiquitin while retaining the ability to bind proline-rich ligands; monoubiquitination of target proteins signals internalization and sorting through the endocytic pathway. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212709 [Multi-domain] Cd Length: 57 Bit Score: 44.23 E-value: 1.10e-05

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                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNP-DWWKGEVA--GVTGLFPTNYVK 1126
Cdd:cd11775     2 RGKVLYDFDAQSDDELTVKEGDVVYILDDKKSkDWWMVENVstGKEGVVPASYIE 56

First Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the first SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212715 [Multi-domain] Cd Length: 53 Bit Score: 44.25 E-value: 1.12e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  753 RALYPFTARNSDELTLEADCFI----QVDEStvretgWLYGSYSGNRGWFPESYAE 804
Cdd:cd11781     3 RALYPFKAQSAKELSLKKGDIIyirrQIDKN------WYEGEHNGRVGIFPASYVE 52

First Src homology 3 domain (or SH3A) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The first SH3 domain (or SH3A) of ITSN2 is expected to bind many protein partners, similar to ITSN1 which has been shown to bind Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212921 [Multi-domain] Cd Length: 57 Bit Score: 44.09 E-value: 1.16e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKD--NPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11988     6 ALYPFEARNHDEMSFNAGDIIQVDEKTvgEPGWLYGSFQGNFGWFPCNYVE 56

Src homology 3 domain of Brk (Breast tumor kinase) Protein Tyrosine Kinase (PTK), also called PTK6; Brk is a cytoplasmic (or non-receptor) PTK with limited homology to Src kinases. It has been found to be overexpressed in a majority of breast tumors. It plays roles in normal cell differentiation, proliferation, survival, migration, and cell cycle progression. Brk substrates include RNA-binding proteins (SLM-1/2, Sam68), transcription factors (STAT3/5), and signaling molecules (Akt, paxillin, IRS-4). Src kinases in general contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr; they are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation site. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212781 [Multi-domain] Cd Length: 58 Bit Score: 44.47 E-value: 1.16e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNpDWW----KGEVAGVT--GLFPTNYV 1125
Cdd:cd11847     3 KALWDFKARGDEELSFQAGDQFRIAERSG-DWWtalkLDRAGGVVaqGFVPNNYL 56

Src Homology 3 domain of beta-Pak Interactive eXchange factor; Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212994 [Multi-domain] Cd Length: 54 Bit Score: 44.29 E-value: 1.19e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVdeSTVRETGWLYGSYSGNRGWFPESY 802
Cdd:cd12061     3 RAKFNFQQTNEDELSFSKGDVIHV--TRVEEGGWWEGTHNGRTGWFPSNY 50

First Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212861 Cd Length: 54 Bit Score: 44.14 E-value: 1.35e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11928     5 ALYSYEGKEPGDLKFNKGDIIILRRKVDENWYHGELNGCHGFLPASYIQC 54

Second Src homology 3 domain (or SH3B) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212922 [Multi-domain] Cd Length: 52 Bit Score: 43.94 E-value: 1.36e-05

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11989     4 ALYPWRAKKDNHLNFNKNDVITVLEQQDMWWFGEVQGQKGWFPKSYVK 51

Src homology 3 domain of Phospholipase C (PLC) gamma; PLC catalyzes the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG) in response to various receptors. Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma catalyzes this reaction in tyrosine kinase-dependent signaling pathways. It is activated and recruited to its substrate at the membrane. Vertebrates contain two forms of PLCgamma, PLCgamma1, which is widely expressed, and PLCgamma2, which is primarily found in haematopoietic cells. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212759 [Multi-domain] Cd Length: 54 Bit Score: 43.86 E-value: 1.46e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKE-GEWWRGCIGDQ-TGLFPSNYVK 983
Cdd:cd11825     4 ALYDYRAQRPDELSFCKHAIITNVEKEdGGWWRGDYGGKkQKWFPANYVE 53

Second Src homology 3 domain (or SH3B) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212923 [Multi-domain] Cd Length: 52 Bit Score: 43.88 E-value: 1.51e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNpDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11990     4 ALCSWTAKKDNHLNFSKNDIITVLEQQE-NWWFGEVHGGRGWFPKSYVKL 52

Src homology 3 domain of Type I fungal Myosins; Type I myosins (myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Saccharomyces cerevisiae has two myosins-I, Myo3 and Myo5, which are involved in endocytosis and the polarization of the actin cytoskeleton. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212792 [Multi-domain] Cd Length: 55 Bit Score: 43.91 E-value: 1.51e-05

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                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKE-GEWWRGCIGDQT--GLFPSNYVKP 984
Cdd:cd11858     2 YKALYDFAGSVANELSLKKDDIVYIVQKEdNGWWLAKKLDESkeGWVPAAYLEE 55

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or SH3P2, is a signaling protein containing SH3 and ankyrin-repeat domains. It acts through a Src-related pathway to enhance the formation of osteoclasts and bone resorption. It also acts as a negative regulator of cell motility. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212706 [Multi-domain] Cd Length: 53 Bit Score: 43.83 E-value: 1.54e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11772     2 FRALYDYEAQHPDELSFEEGDLLYISDKS--DPNWWKATCGGKTGLIPSNYVE 52

C2 domain first repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); MCTPs are involved in Ca2+ signaling at the membrane. MCTP is composed of a variable N-terminal sequence, three C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-II topology.

Pssm-ID: 176007 [Multi-domain] Cd Length: 121 Bit Score: 45.73 E-value: 1.58e-05

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146 1529 NGKSNPYCELTM-GAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLcLTVFERDQFSPDDFLGRTEVPVATIKKDQ 1604
Cdd:cd04042    18 GGTSDPYVKFKYgGKTVYKSKTIYKNLNPVWDEKFTLPIEDVTQPLY-IKVFDYDRGLTDDFMGSAFVDLSTLELNK 93

Src Homology 3 (SH3) domain of Apoptosis Stimulating of p53 protein 2; ASPP2 is the full length form of the previously-identified tumor supressor, p53-binding protein 2 (p53BP2). ASPP2 activates the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73). It plays a central role in regulating apoptosis and cell growth; ASPP2-deficient mice show postnatal death. Downregulated expression of ASPP2 is frequently found in breast tumors, lung cancer, and diffuse large B-cell lymphoma where it is correlated with a poor clinical outcome. ASPP2 contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of ASPP2 contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212886 [Multi-domain] Cd Length: 57 Bit Score: 43.79 E-value: 1.59e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPD---WWKGEVAGVTGLFPTN 1123
Cdd:cd11953     3 VYALWDYEGESDDELSFKEGDCMTILRREDEDeteWWWARLNDKEGYVPRN 53

Second Src Homology 3 domain (SH3B) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CD2AP. SH3B binds to c-Cbl in a site (TPSSRPLR is the core binding motif) distinct from the c-Cbl/SH3A binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212987 [Multi-domain] Cd Length: 55 Bit Score: 43.80 E-value: 1.61e-05

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  937 LYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd12054     6 LFEYVPQNEDELELKVGDIIDINEEvEEGWWSGTLNGKSGLFPSNFVK 53

Src homology 3 domain of Phospholipase C (PLC) gamma 1; PLCgamma1 is widely expressed and is essential in growth and development. It is activated by the TrkA receptor tyrosine kinase and functions as a key regulator of cell differentiation. It is also the predominant PLCgamma in T cells and is required for T cell and NK cell function. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212903 Cd Length: 60 Bit Score: 43.82 E-value: 1.71e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRG-CIGDQTGLFPSNYVK 983
Cdd:cd11970     8 ALFDYKAQREDELTFTKNAIIQNVEKqEGGWWRGdYGGKKQLWFPSNYVE 57

Src homology 3 domain of Slit-Robo GTPase Activating Protein 4; srGAP4, also called ARHGAP4, is highly expressed in hematopoietic cells and may play a role in lymphocyte differentiation. It is able to stimulate the GTPase activity of Rac1, Cdc42, and RhoA. In the nervous system, srGAP4 has been detected in differentiating neurites and may be involved in axon and dendritic growth. srGAPs are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212889 [Multi-domain] Cd Length: 55 Bit Score: 43.67 E-value: 1.73e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYV 982
Cdd:cd11956     3 EAVACFDYTGRTAQELSFKRGDVLLLHSKaSSDWWRGEHNGMRGLIPHKYI 53

First or N-terminal Src homology 3 domain of the p47phox subunit of NADPH oxidase, also called Neutrophil Cytosolic Factor 1; p47phox, or NCF1, is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p47phox is required for activation of NADH oxidase and plays a role in translocation. It contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), a polybasic/autoinhibitory region, and a C-terminal proline-rich region (PRR). This model characterizes the first SH3 domain (or N-SH3) of p47phox. In its inactive state, the tandem SH3 domains interact intramolecularly with the autoinhibitory region; upon activation, the tandem SH3 domains are exposed through a conformational change, resulting in their binding to the PRR of p22phox and the activation of NADPH oxidase. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212954 [Multi-domain] Cd Length: 53 Bit Score: 43.41 E-value: 1.84e-05

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLEKQEN-WWYGELKEKRGWFPCSHV 903
Cdd:cd12021     4 AIADYEKSSKSEMALKTGDVVEVVEKSENgWWFCQLKAKRGWVPASYL 51

Second Src Homology 3 domain of FCH and double SH3 domains protein 1; FCHSD1 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212828 Cd Length: 58 Bit Score: 43.80 E-value: 1.85e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNK--DNPD--WWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11895     4 ALYSYTGQSPEELSFPEGALIRLLPRaqDGVDdgFWRGEFGGRVGVFPSLLVE 56

Uncharacterized N-terminal coiled-coil domain of peptidoglycan hydrolase CwlO [Function unknown];

Pssm-ID: 443091 [Multi-domain] Cd Length: 379 Bit Score: 48.67 E-value: 2.05e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  458 QTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKskrqgqwAELELINQRrdvcitdINSLQLQFDEMQRQ 537
Cdd:COG3883    15 DPQIQAKQKELSELQAELEAAQAELDALQAELEELNEEYNELQ-------AELEALQAE-------IDKLQAEIAEAEAE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  538 LNQLgpeKQRLADRLVH-FTQNISSPLINDVKQSvcekdRSCRKLKEQLDVLERETTAKLSQMEQYNKEIKELRQKQSQQ 616
Cdd:COG3883    81 IEER---REELGERARAlYRSGGSVSYLDVLLGS-----ESFSDFLDRLSALSKIADADADLLEELKADKAELEAKKAEL 152

                         170       180
                  ....*....|....*....|...
gi 688602146  617 QDVLEQLRRVRSD---KLKELQR 636
Cdd:COG3883   153 EAKLAELEALKAEleaAKAELEA 175

C2 domain first repeat present in Rabphilin and Double C2 domain; Rabphilin is found neurons and in neuroendrocrine cells, while Doc2 is found not only in the brain but in tissues, including mast cells, chromaffin cells, and osteoblasts. Rabphilin and Doc2s share highly homologous tandem C2 domains, although their N-terminal structures are completely different: rabphilin contains an N-terminal Rab-binding domain (RBD),7 whereas Doc2 contains an N-terminal Munc13-1-interacting domain (MID). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

Pssm-ID: 176000 [Multi-domain] Cd Length: 123 Bit Score: 45.35 E-value: 2.11e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1512 RLLVTVLEATELKPCKPNGKSNPYCELTM--GAQCYT---SRHQPDTLNPKWSFNCQFF---IKDLYQDVLCLTVFERDQ 1583
Cdd:cd04035    16 ALHCTIIRAKGLKAMDANGLSDPYVKLNLlpGASKATklrTKTVHKTRNPEFNETLTYYgitEEDIQRKTLRLLVLDEDR 95

                          90       100
                  ....*....|....*....|.
gi 688602146 1584 FSpDDFLGRTEVPVATIKKDQ 1604
Cdd:cd04035    96 FG-NDFLGETRIPLKKLKPNQ 115

Second C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212894 [Multi-domain] Cd Length: 53 Bit Score: 43.28 E-value: 2.15e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLE-KQENWWYGELKEKRGWFPCSHVS 904
Cdd:cd11961     2 AKALYDYDAAEDNELSFFENDKIINIEfVDDDWWLGECHGSRGLFPSNYVE 52

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212754 [Multi-domain] Cd Length: 54 Bit Score: 43.22 E-value: 2.17e-05

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLE-KQENWWYGELKEKRGWFPCSHVS 904
Cdd:cd11820     5 ALYDFEAAEDNELTFKAGEIITVLDdSDPNWWKGSNHRGEGLFPANFVT 53

Src Homology 3 domain of Mixed Lineage Kinase 4; MLK4 is a Serine/Threonine Kinase (STK), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. MLK4 contains an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212991 [Multi-domain] Cd Length: 58 Bit Score: 43.39 E-value: 2.23e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGE------WWRGCIGDQTGLFPSNYVKP 984
Cdd:cd12058     2 WTALYDYEASGEDELSLRRGDVVEVLSQDAAvsgddgWWAGKIRHRLGIFPANYVTR 58

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 429575 [Multi-domain] Cd Length: 54 Bit Score: 43.35 E-value: 2.26e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 688602146  1010 ATTPEQLSLTPGQLIVVLHKNSNSWWLGELqargkKRKKGWFQSSNVRLL 1059
Cdd:pfam07653   10 GTDKNGLTLKKGDVVKVLGKDNDGWWEGET-----GGRVGLVPSTAVEEI 54

Src homology 3 domain of Brk (Breast tumor kinase) Protein Tyrosine Kinase (PTK), also called PTK6; Brk is a cytoplasmic (or non-receptor) PTK with limited homology to Src kinases. It has been found to be overexpressed in a majority of breast tumors. It plays roles in normal cell differentiation, proliferation, survival, migration, and cell cycle progression. Brk substrates include RNA-binding proteins (SLM-1/2, Sam68), transcription factors (STAT3/5), and signaling molecules (Akt, paxillin, IRS-4). Src kinases in general contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr; they are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation site. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212781 [Multi-domain] Cd Length: 58 Bit Score: 43.32 E-value: 2.30e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGEWWRGCIGDQ------TGLFPSNYV 982
Cdd:cd11847     2 YKALWDFKARGDEELSFQAGDQFRIAERSGDWWTALKLDRaggvvaQGFVPNNYL 56

Src homology 3 domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; PSTPIP1, also called CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212758 [Multi-domain] Cd Length: 53 Bit Score: 43.13 E-value: 2.39e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11824     1 KYSVLYDYTAQEDDELSISKGDVVAVIEKGEDgWWTVERNGQKGLVPGTYLE 52

Src homology 3 domain of Endophilin-A; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain three endophilin-A isoforms (A1, A2, and A3). Endophilin-A proteins are enriched in the brain and play multiple roles in receptor-mediated endocytosis. They tubulate membranes and regulate calcium influx into neurons to trigger the activation of the endocytic machinery. They are also involved in the sorting of plasma membrane proteins, actin filament assembly, and the uncoating of clathrin-coated vesicles for fusion with endosomes. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212737 [Multi-domain] Cd Length: 55 Bit Score: 43.40 E-value: 2.47e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHVSVV 906
Cdd:cd11803     2 CCRALYDFEPENEGELGFKEGDIITLTNQiDENWYEGMVNGQSGFFPVNYVEVL 55

Src Homology 3 domain of Sdc25/Cdc25 guanine nucleotide exchange factors; This subfamily is composed of the Saccharomyces cerevisiae guanine nucleotide exchange factors (GEFs) Sdc25 and Cdc25, and similar proteins. These GEFs regulate Ras by stimulating the GDP/GTP exchange on Ras. Cdc25 is involved in the Ras/PKA pathway that plays an important role in the regulation of metabolism, stress responses, and proliferation, depending on available nutrients and conditions. Proteins in this subfamily contain an N-terminal SH3 domain as well as REM (Ras exchanger motif) and RasGEF domains at the C-terminus. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212816 Cd Length: 55 Bit Score: 43.04 E-value: 2.58e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQT-----GLFPSNY 981
Cdd:cd11883     3 VALYDFTPKSKNQLSFKAGDIIYVLNKdPSGWWDGVIISSSgkvkrGWFPSNY 55

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member, Embryonal Fyn-associated Substrate; EFS is also called HEFS, CASS3 (Cas scaffolding protein family member 3) or SIN (Src-interacting protein). It was identified based on interactions with the Src kinases, Fyn and Yes. It plays a role in thymocyte development and acts as a negative regulator of T cell proliferation. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212936 Cd Length: 62 Bit Score: 43.34 E-value: 2.72e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPD---WWKGEVAGVTGLFPTNYVKMTTE 1130
Cdd:cd12003     5 ALYDNAAESPEELSFRRGDVLMVLKREHGSlpgWWLCSLHGQQGIAPANRLRLLPT 60

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; N-terminal SH3 domain of the uncharacterized protein SH3 domain-containing protein 21, and similar uncharacterized domains, it belongs to the CD2AP-like_3 subfamily of proteins. The CD2AP-like_3 subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213018 [Multi-domain] Cd Length: 55 Bit Score: 43.22 E-value: 2.74e-05

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 688602146  858 LCEWSAKTDSHLGFCKDDIITVLEKQ---ENWWYGELKEKRGWFP 899
Cdd:cd12142     5 LFDYNPVAPDELALKKGDVIEVISKEtedEGWWEGELNGRRGFFP 49

Src Homology 3 domain of Tec-like Protein Tyrosine Kinases; The Tec (Tyrosine kinase expressed in hepatocellular carcinoma) subfamily is composed of Tec, Btk, Bmx (Etk), Itk (Tsk, Emt), Rlk (Txk), and similar proteins. They are cytoplasmic (or nonreceptor) tyr kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Most Tec subfamily members (except Rlk) also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, some members contain the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. Tec kinases are expressed mainly by haematopoietic cells, although Tec and Bmx are also found in endothelial cells. B-cells express Btk and Tec, while T-cells express Itk, Txk, and Tec. Collectively, Tec kinases are expressed in a variety of myeloid cells such as mast cells, platelets, macrophages, and dendritic cells. Each Tec kinase shows a distinct cell-type pattern of expression. The function of Tec kinases in lymphoid cells have been studied extensively. They play important roles in the development, differentiation, maturation, regulation, survival, and function of B-cells and T-cells. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212702 [Multi-domain] Cd Length: 54 Bit Score: 43.03 E-value: 2.82e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGD-QTGLFPSNYVKP 984
Cdd:cd11768     3 VALYDFQPIEPGDLPLEKGEEYVVLDDSNEhWWRARDKNgNEGYIPSNYVTE 54

C2A domain first repeat present in Synaptotagmin 8; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

Pssm-ID: 176033 [Multi-domain] Cd Length: 124 Bit Score: 45.09 E-value: 3.00e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1507 NSGIGRLLVTVLEATELKPCKPNGKSNPYCELTMGAQCYT---SRHQPDTLNPKW--SFNCQFFIKDLYQDVLCLTVFER 1581
Cdd:cd08387    12 DKDMGILNVKLIQARNLQPRDFSGTADPYCKVRLLPDRSNtkqSKIHKKTLNPEFdeSFVFEVPPQELPKRTLEVLLYDF 91

                          90       100       110
                  ....*....|....*....|....*....|...
gi 688602146 1582 DQFSPDDFLGRTEVPVATIkkDQDGKGPLVRRL 1614
Cdd:cd08387    92 DQFSRDECIGVVELPLAEV--DLSEKLDLWRKI 122

Src homology 3 domain of the CAS (Crk-Associated Substrate) scaffolding protein family member, Breast Cancer Anti-estrogen Resistance 1; BCAR1, also called p130cas or CASS1, is the founding member of the CAS family of scaffolding proteins and was originally identified through its ability to associate with Crk. The name BCAR1 was designated because the human gene was identified in a screen for genes that promote resistance to tamoxifen. It is widely expressed and its deletion is lethal in mice. It plays a role in regulating cell motility, survival, proliferation, transformation, cancer progression, and bacterial pathogenesis. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212934 Cd Length: 68 Bit Score: 43.49 E-value: 3.01e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNP---DWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd12001     7 ALYDNVAESPDELSFRKGDIMTVLERDTQgldGWWLCSLHGRQGIVPGNRLKI 59

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212777 [Multi-domain] Cd Length: 53 Bit Score: 42.79 E-value: 3.02e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  753 RALYPFTARNSDELTLEA-DCFIQVDESTvrETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11843     3 RALYDYEGQESDELSFKAgDILTKLEEED--EQGWCKGRLDGRVGLYPANYVE 53

Septal ring factor EnvC, activator of murein hydrolases AmiA and AmiB [Cell cycle control, cell division, chromosome partitioning];

Pssm-ID: 443969 [Multi-domain] Cd Length: 377 Bit Score: 48.22 E-value: 3.05e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  473 DRKRSLEIELEAVGNKHKQISSQLRDAKSKRQGQWAELELINQRRDVCITDINSLQLQFDEMQRQLNQLGPEKQRLADRL 552
Cdd:COG4942    20 DAAAEAEAELEQLQQEIAELEKELAALKKEEKALLKQLAALERRIAALARRIRALEQELAALEAELAELEKEIAELRAEL 99

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  553 VHFTQNISSPLINDVKQSvcekdrscRKLKEQLdVLERETTAKLSQMEQYNKEIKELRQKQ-SQQQDVLEQLRRVRSDKL 631
Cdd:COG4942   100 EAQKEELAELLRALYRLG--------RQPPLAL-LLSPEDFLDAVRRLQYLKYLAPARREQaEELRADLAELAALRAELE 170

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 688602146  632 KELQRhrkeeeerkrKKEEEAARQAQLEQERLEQEEAERQRKLAQEREAKLREE-----QQRQALARLLEAQEQ 700
Cdd:COG4942   171 AERAE----------LEALLAELEEERAALEALKAERQKLLARLEKELAELAAElaelqQEAEELEALIARLEA 234

Third (or C-terminal) Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the third SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212714 [Multi-domain] Cd Length: 55 Bit Score: 43.06 E-value: 3.07e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKG--EVAGVTGLFPTNYVK 1126
Cdd:cd11780     4 ALYSYTPQNEDELELREGDIVYVMEKCDDGWFVGtsERTGLFGTFPGNYVA 54

Ca2+-dependent lipid-binding protein, contains C2 domain [General function prediction only];

Pssm-ID: 227371 [Multi-domain] Cd Length: 1227 Bit Score: 48.99 E-value: 3.40e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKPCKPNGKSNPYCELTM-GAQCYTSRHQPDTLNPKW--SFNCQFFIKDLyqDVLCLTVFERDQFSPD 1587
Cdd:COG5038  1040 GYLTIMLRSGENLPSSDENGYSDPFVKLFLnEKSVYKTKVVKKTLNPVWneEFTIEVLNRVK--DVLTINVNDWDSGEKN 1117

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 688602146 1588 DFLGRTEVPVATIKKDQ--------DGKGPLVRRLLLH 1617
Cdd:COG5038  1118 DLLGTAEIDLSKLEPGGttnsniplDGKTFIVLDGTLH 1155

Src Homology 3 domain of Cdc42-Interacting Protein 4; This subfamily is composed of Cdc42-Interacting Protein 4 (CIP4), Formin Binding Protein 17 (FBP17), FormiN Binding Protein 1-Like (FNBP1L), and similar proteins. CIP4 and FNBP1L are Cdc42 effectors that bind Wiskott-Aldrich syndrome protein (WASP) and function in endocytosis. CIP4 and FBP17 bind to the Fas ligand and may be implicated in the inflammatory response. CIP4 may also play a role in phagocytosis. It functions downstream of Cdc42 in PDGF-dependent actin reorganization and cell migration, and also regulates the activity of PDGFRbeta. It uses Src as a substrate in regulating the invasiveness of breast tumor cells. CIP4 may also play a role in the pathogenesis of Huntington's disease. Members of this subfamily typically contain an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain, a central Cdc42-binding HR1 domain, and a C-terminal SH3 domain. The SH3 domain of CIP4 associates with Gapex-5, a Rab31 GEF. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212844 [Multi-domain] Cd Length: 55 Bit Score: 43.02 E-value: 3.41e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWW----KGEvaGVTGLFPTNYVKM 1127
Cdd:cd11911     1 TCTALYDFDGTSEGTLSMEEGEILLVLEEDGGDGWtrvrKNN--GDEGYVPTSYIEV 55

Src Homology 3 domain of Sorting Nexin 9 and similar proteins; Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. This subfamily consists of SH3 domain containing SNXs including SNX9, SNX18, SNX33, and similar proteins. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212697 [Multi-domain] Cd Length: 55 Bit Score: 42.70 E-value: 3.46e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEK--EGEWWRGC-IGDQTGLFPSNYVKP 984
Cdd:cd11763     4 ALYDFDSQPSGELSLRAGEVLTITRQdvGDGWLEGRnSRGEVGLFPSSYVEI 55

Predicted nucleic acid-binding protein DR0291, contains C4-type Zn-ribbon domain [General function prediction only];

Pssm-ID: 441187 [Multi-domain] Cd Length: 236 Bit Score: 47.23 E-value: 3.50e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  468 IQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKskrqgqwAELELINQRRDVCITDINSLQLQFDEMQRQLNQLGPEKQr 547
Cdd:COG1579    19 LDRLEHRLKELPAELAELEDELAALEARLEAAK-------TELEDLEKEIKRLELEIEEVEARIKKYEEQLGNVRNNKE- 90

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  548 ladrLVHFTQNISSplindvkqsvcekdrscrkLKEQLDVLERETTAKLSQMEQYNKEIKELRQKQSQQQDVLEQLRRVR 627
Cdd:COG1579    91 ----YEALQKEIES-------------------LKRRISDLEDEILELMERIEELEEELAELEAELAELEAELEEKKAEL 147


                  ....*....
gi 688602146  628 SDKLKELQR 636
Cdd:COG1579   148 DEELAELEA 156

Src homology 3 domain of Cortactin and related proteins; This subfamily includes cortactin, Abp1 (actin-binding protein 1), hematopoietic lineage cell-specific protein 1 (HS1), and similar proteins. These proteins are involved in regulating actin dynamics through direct or indirect interaction with the Arp2/3 complex, which is required to initiate actin polymerization. They all contain at least one C-terminal SH3 domain. Cortactin and HS1 bind Arp2/3 and actin through an N-terminal region that contains an acidic domain and several copies of a repeat domain found in cortactin and HS1. Abp1 binds actin via an N-terminal actin-depolymerizing factor (ADF) homology domain. Yeast Abp1 binds Arp2/3 directly through two acidic domains. Mammalian Abp1 does not directly interact with Arp2/3; instead, it regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. The C-terminal region of these proteins acts as an adaptor or scaffold that can connect membrane trafficking and signaling proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212753 [Multi-domain] Cd Length: 54 Bit Score: 42.69 E-value: 3.54e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKE-KRGWFPCSHVS 904
Cdd:cd11819     1 RAKALYDYQAAEDNEISFVEGDIITQIEQiDEGWWLGVNAKgQKGLFPANYVE 53

Fifth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212752 [Multi-domain] Cd Length: 50 Bit Score: 42.86 E-value: 3.56e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDESTVREtgWLYGSYSGNRGWFPESY 802
Cdd:cd11818     3 RALYDFTGENEDELSFKAGDIITELESIDEE--WMSGELRGKSGIFPKNF 50

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the peroxisomal membrane, contains two transmembrane regions and a C-terminal SH3 domain. It binds to the peroxisomal targeting type I (PTS1) receptor Pex5p and the docking factor Pex14p through its SH3 domain. It is essential for both PTS1 and PTS2 protein import pathways into the peroxisomal matrix. Pex13p binds Pex14p, which contains a PxxP motif, in a classical fashion to the proline-rich ligand binding site of its SH3 domain. It binds the WxxxF/Y motif of Pex5p in a novel site that does not compete with Pex14p binding. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212705 [Multi-domain] Cd Length: 60 Bit Score: 43.03 E-value: 3.73e-05

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 688602146  869 LGFCKDDIITVLEKQE------NWWYGELKEKR-GWFPCSHVSV 905
Cdd:cd11771    17 LSLKKGDIVAVLSKTDplgrdsEWWKGRTRDGRiGWFPSNYVEV 60

Src Homology 3 domain of alpha-Pak Interactive eXchange factor; Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6) or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212993 Cd Length: 58 Bit Score: 43.07 E-value: 3.77e-05

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 688602146  864 KTDSHLGFCKDDIITVLEKQEN-WWYGELKEKRGWFPCSHV 903
Cdd:cd12060    13 TNEDELSVCKGDIIYVTRVEEGgWWEGTLNGKTGWFPSNYV 53

Src homology 3 domain of SH3 protein interacting with Nck, 90 kDa (SPIN90); SPIN90 is also called NCK interacting protein with SH3 domain (NCKIPSD), Dia-interacting protein (DIP), 54 kDa vimentin-interacting protein (VIP54), or WASP-interacting SH3-domain protein (WISH). It is an F-actin binding protein that regulates actin polymerization and endocytosis. It associates with the Arp2/3 complex near actin filaments and determines filament localization at the leading edge of lamellipodia. SPIN90 is expressed in the early stages of neuronal differentiation and plays a role in regulating growth cone dynamics and neurite outgrowth. It also interacts with IRSp53 and regulates cell motility by playing a role in the formation of membrane protrusions. SPIN90 contains an N-terminal SH3 domain, a proline-rich domain, and a C-terminal VCA (verprolin-homology and cofilin-like acidic) domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212783 [Multi-domain] Cd Length: 53 Bit Score: 42.69 E-value: 3.84e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGEWWRGCI--GDQTGLFPSNYVK 983
Cdd:cd11849     2 YRALYDFKSAEPNTLSFSEGETFLLLERSNAHWWLVTnhSGETGYVPANYVK 53

Src homology 3 domain of Signal Transducing Adaptor Molecule 1; STAM1 is part of the endosomal sorting complex required for transport (ESCRT-0) and is involved in sorting ubiquitinated cargo proteins from the endosome. It may also be involved in the regulation of IL2 and GM-CSF mediated signaling, and has been implicated in neural cell survival. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212897 [Multi-domain] Cd Length: 55 Bit Score: 42.63 E-value: 3.92e-05

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKEKRGWFPCSHVS 904
Cdd:cd11964     5 AIYDFEAAEDNELTFKAGDIITILDDSDpNWWKGETPQGTGLFPSNFVT 53

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The N-terminal SH3 domain of GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212738 [Multi-domain] Cd Length: 52 Bit Score: 42.73 E-value: 4.09e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQE--NWWYGELKEKRGWFPCSHV 903
Cdd:cd11804     1 EAVAKHDFKATAEDELSFKKGSILKVLNMEDdpNWYKAELDGKEGLIPKNYI 52

C2 domain second repeat present in Synaptotagmin-like proteins; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 176015 [Multi-domain] Cd Length: 105 Bit Score: 44.09 E-value: 4.13e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1513 LLVTVLE-ATELKPCKPNGKSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQFSPddfLG 1591
Cdd:cd04050     1 LLFVYLDsAKNLPLAKSTKEPSPYVELTVGKTTQKSKVKERTNNPVWEEGFTFLVRNPENQELEIEVKDDKTGKS---LG 77

                          90
                  ....*....|....
gi 688602146 1592 RTEVPVATIKKDQD 1605
Cdd:cd04050    78 SLTLPLSELLKEPD 91

First Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212695 [Multi-domain] Cd Length: 57 Bit Score: 42.74 E-value: 4.15e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 688602146 1073 LCQVIamYDYKAANKDEMSFQKGQLITVLNKDNPDWW------KGEVagvtGLFPTNYV 1125
Cdd:cd11761     3 TCKVL--YSYEAQRPDELTITEGEELEVIEDGDGDGWvkarnkSGEV----GYVPENYL 55

Second Src Homology 3 domain of SH3 domain containing ring finger 2; SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal RING finger domain and three SH3 domains. This model represents the second SH3 domain, located C-terminal of the first SH3 domain at the N-terminal half, of SH3RF2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212865 Cd Length: 57 Bit Score: 42.52 E-value: 4.24e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146 1073 LCQVIAMYDYKAANKDE----MSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11932     1 LCRALYNFDLKEKNREEskdcLKFQKDDIITVISRVDENWAEGKLGDQVGIFPILFV 57

Src Homology 3 domain of Membrane Protein, Palmitoylated (or MAGUK p55 subfamily member) proteins; The MPP/p55 subfamily of MAGUK (membrane-associated guanylate kinase) proteins includes at least eight vertebrate members (MPP1-7 and CASK), four Drosophila proteins (Stardust, Varicose, CASK and Skiff), and other similar proteins; they all contain one each of the core of three domains characteristic of MAGUK proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, most members except for MPP1 contain N-terminal L27 domains and some also contain a Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. CASK has an additional calmodulin-dependent kinase (CaMK)-like domain at the N-terminus. Members of this subfamily are scaffolding proteins that play important roles in regulating and establishing cell polarity, cell adhesion, and synaptic targeting and transmission, among others. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212796 Cd Length: 61 Bit Score: 42.57 E-value: 4.38e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146 1078 AMYDYKAANKDEM-------SFQKGQLITVLNKDNPDWWK----GEVAGVTGLFPT 1122
Cdd:cd11862     4 ALFDYDPEEDPLIpckeaglSFKKGDILQIVNQDDPNWWQarkvGDPNGRAGLIPS 59

Fourth Src homology 3 domain (or SH3D) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212926 Cd Length: 65 Bit Score: 42.80 E-value: 4.39e-05

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1073 LCQVIAmyDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAG-----VTGLFPTNYVKMTT 1129
Cdd:cd11993     5 IAQVIA--SYTATGPEQLTLAPGQLILIRKKNPGGWWEGELQArgkkrQIGWFPANYVKLLS 64

AmiB activator; Provisional

Pssm-ID: 236942 [Multi-domain] Cd Length: 428 Bit Score: 47.77 E-value: 4.41e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  458 QTQKEKEQnDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSkrqgqwaELELINQRRDVCITDINSLQLQFDEMQR- 536
Cdd:PRK11637   54 QDIAAKEK-SVRQQQQQRASLLAQLKKQEEAISQASRKLRETQN-------TLNQLNKQIDELNASIAKLEQQQAAQERl 125

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  537 ---QLN-----------QL---GPEKQRLADRLVHFTqnisspLINDVKQSVCEKDRSCRKlkeqldvlerETTAKLSQM 599
Cdd:PRK11637  126 laaQLDaafrqgehtglQLilsGEESQRGERILAYFG------YLNQARQETIAELKQTRE----------ELAAQKAEL 189

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  600 EQYNKEIKELRQKQSQQQDVLEQLRRVRSDKLKELQrhrkeeeerkrkkeeEAARQAQLEQERLEQEEAERQRKLAQ-ER 678
Cdd:PRK11637  190 EEKQSQQKTLLYEQQAQQQKLEQARNERKKTLTGLE---------------SSLQKDQQQLSELRANESRLRDSIARaER 254

                         250       260
                  ....*....|....*....|..
gi 688602146  679 EAKLREEQQRQALARLLEAQEQ 700
Cdd:PRK11637  255 EAKARAEREAREAARVRDKQKQ 276

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212909 [Multi-domain] Cd Length: 54 Bit Score: 42.62 E-value: 4.44e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVdESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11976     1 TAKARYDFCARDRSELSLKEGDIIKI-LNKKGQQGWWRGEIYGRVGWFPANYVE 53

Src Homology 3 domain of Membrane Protein, Palmitoylated 1 (or MAGUK p55 subfamily member 1); MPP1, also called 55 kDa erythrocyte membrane protein (p55), is a ubiquitously-expressed scaffolding protein that plays roles in regulating neutrophil polarity, cell shape, hair cell development, and neural development and patterning of the retina. It was originally identified as an erythrocyte protein that stabilizes the actin cytoskeleton to the plasma membrane by forming a complex with 4.1R protein and glycophorin C. MPP1 is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains the three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213013 Cd Length: 62 Bit Score: 42.63 E-value: 4.46e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146 1078 AMYDYKAANKD-------EMSFQKGQLITVLNKDNPDWWKGEV----AGVTGLFPT 1122
Cdd:cd12080     4 AQFDYDPKKDNlipckeaGLKFQTGDIIQIINKDDSNWWQGRVegsgEESAGLIPS 59

Src Homology 3 domain of Myosin XV; This subfamily is composed of proteins with similarity to Myosin XVa. Myosin XVa is an unconventional myosin that is critical for the normal growth of mechanosensory stereocilia of inner ear hair cells. Mutations in the myosin XVa gene are associated with nonsyndromic hearing loss. Myosin XVa contains a unique N-terminal extension followed by a motor domain, light chain-binding IQ motifs, and a tail consisting of a pair of MyTH4-FERM tandems separated by a SH3 domain, and a PDZ domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212817 [Multi-domain] Cd Length: 56 Bit Score: 42.70 E-value: 4.49e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  753 RALYPFTARNSDELTLEADCFIQV-DESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11884     3 VAVRAYITRDQTLLSFHKGDVIKLlPKEGPLDPGWLFGTLDGRSGAFPKEYVQ 55

Src homology 3 domain of Growth Arrest Specific protein 7; GAS7 is mainly expressed in the brain and is required for neurite outgrowth. It may also play a role in the protection and migration of embryonic stem cells. Treatment-related acute myeloid leukemia (AML) has been reported resulting from mixed-lineage leukemia (MLL)-GAS7 translocations as a complication of primary cancer treatment. GAS7 contains an N-terminal SH3 domain, followed by a WW domain, and a central F-BAR domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212763 [Multi-domain] Cd Length: 52 Bit Score: 42.50 E-value: 4.64e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  753 RALYPFTA-RNSDELTLEADCFIQVDEstVRETGWLYGSYSGNRGWFPESY 802
Cdd:cd11829     3 RTLYAFTGeQHQQGLSFEAGELIRVLQ--APDGGWWEGEKDGLRGWFPASY 51

Second Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212856 [Multi-domain] Cd Length: 57 Bit Score: 42.60 E-value: 4.70e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVT--GLFPTNYVKM 1127
Cdd:cd11923     2 EAVAKYNFNADTNVELSLRKGDRVVLLKQVDQNWYEGKIPGTNrqGIFPVSYVEV 56

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212909 [Multi-domain] Cd Length: 54 Bit Score: 42.62 E-value: 4.71e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLEK--QENWWYGELKEKRGWFPCSHV 903
Cdd:cd11976     2 AKARYDFCARDRSELSLKEGDIIKILNKkgQQGWWRGEIYGRVGWFPANYV 52

C-terminal Src Homology 3 domain of Nebulette and LIM-nebulette (or Lasp2); Nebulette is a cardiac-specific protein that localizes to the Z-disc. It interacts with tropomyosin and is important in stabilizing actin thin filaments in cardiac muscles. Polymorphisms in the nebulette gene are associated with dilated cardiomyopathy, with some mutations resulting in severe heart failure. Nebulette is a 107kD protein that contains an N-terminal acidic region, multiple nebulin repeats, and a C-terminal SH3 domain. LIM-nebulette, also called Lasp2 (LIM and SH3 domain protein 2), is an alternatively spliced variant of nebulette. Although it shares a gene with nebulette, Lasp2 is not transcribed from a muscle-specific promoter, giving rise to its multiple tissue expression pattern with highest amounts in the brain. It can crosslink actin filaments and it affects cell spreading. Lasp2 is a 34kD protein containing an N-terminal LIM domain, three nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212868 [Multi-domain] Cd Length: 58 Bit Score: 42.68 E-value: 4.87e-05

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 688602146  750 TTYRALYPFTARNSDELTLEADCFIQ----VDEstvretGWLYGSY--SGNRGWFPESYAE 804
Cdd:cd11935     1 RTYRAMYDYSAQDEDEVSFRDGDYIVnvqpIDE------GWMYGTVqrTGRTGMLPANYIE 55

Fifth Src homology 3 domain (or SH3E) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212929 [Multi-domain] Cd Length: 54 Bit Score: 42.28 E-value: 4.92e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11996     2 QVIAMYDYTANNEDELSFSKGQLINVLNKDDpDWWQGEINGVTGLFPSNYVKM 54

Third Src homology 3 domain (or SH3C) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. The SH3C of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212772 [Multi-domain] Cd Length: 52 Bit Score: 42.40 E-value: 4.97e-05

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLEKQENWWYGELKEKRGWFPCSHV 903
Cdd:cd11838     3 IALYPYESNEPGDLTFNAGDVILVTKKDGEWWTGTIGDRTGIFPSNYV 50

Third Src Homology 3 domain (SH3C) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CD2AP. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212989 [Multi-domain] Cd Length: 57 Bit Score: 42.50 E-value: 5.37e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKE-GE--WWRGCIGDQTGLFPSNYV 982
Cdd:cd12056     6 ALFHYEGTNEDELDFKEGEIILIISKDtGEpgWWKGELNGKEGVFPDNFV 55

Src Homology 3 domain of Sorting Nexin 33; SNX33 interacts with Wiskott-Aldrich syndrome protein (WASP) and plays a role in the maintenance of cell shape and cell cycle progression. It modulates the shedding and endocytosis of cellular prion protein (PrP(c)) and amyloid precursor protein (APP). SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX33 also contains BAR and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212829 [Multi-domain] Cd Length: 55 Bit Score: 42.26 E-value: 5.54e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPD-WWKGEVA-GVTGLFPTNYVKM 1127
Cdd:cd11896     4 ALYSFQSENKEEINIQENEELVIFSENSLDgWLQGQNSrGETGLFPASYVEI 55

Third Src Homology 3 domain (SH3C) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CD2AP. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212989 [Multi-domain] Cd Length: 57 Bit Score: 42.50 E-value: 5.64e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDESTVRETGWLYGSYSGNRGWFPESYA 803
Cdd:cd12056     5 KALFHYEGTNEDELDFKEGEIILIISKDTGEPGWWKGELNGKEGVFPDNFV 55

Third Src Homology 3 domain of SH3 domain containing ring finger 1, an E3 ubiquitin-protein ligase; SH3RF1 is also called POSH (Plenty of SH3s) or SH3MD2 (SH3 multiple domains protein 2). It is a scaffold protein that acts as an E3 ubiquitin-protein ligase. It plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. It contains an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle, of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212859 [Multi-domain] Cd Length: 55 Bit Score: 42.26 E-value: 5.78e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEV--AGVTGLFPTNYV 1125
Cdd:cd11926     3 VAIYPYTPRKEDELELRKGEMFLVFERCQDGWFKGTSmhTSKIGVFPGNYV 53

Src homology 3 domains of Rab3-interacting molecules (RIMs) binding proteins; RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2. RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3. RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery. RIM-BPs contain three SH3 domains and two to three fibronectin III repeats. Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3. RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis. The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212785 Cd Length: 62 Bit Score: 42.30 E-value: 5.83e-05

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1076 VIAMYDYKAAN-------KDEMSFQKGQLITVL-NKDNPDWWKGEV-AGVTGLFPTNYVK 1126
Cdd:cd11851     2 MVALYDYNPETmspnddpEEELSFHAGDVVRVYgPMDEDGFYYGELeGGRKGLVPSNFVQ 61

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 44.40 E-value: 6.06e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 688602146  226 RQLFNSLDKLMSGYLSGPQVRNALTASNLTQTQLATIWFLADVDRDGQLRAEEFILAMH 284
Cdd:COG5126    72 RAAFDLLDTDGDGKISADEFRRLLTALGVSEEEADELFARLDTDGDGKISFEEFVAAVR 130

Src homology 3 domain of Phospholipase C (PLC) gamma 1; PLCgamma1 is widely expressed and is essential in growth and development. It is activated by the TrkA receptor tyrosine kinase and functions as a key regulator of cell differentiation. It is also the predominant PLCgamma in T cells and is required for T cell and NK cell function. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212903 Cd Length: 60 Bit Score: 42.28 E-value: 6.18e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDEStvRETGWLYGSYSGNRG-WFPESYAE 804
Cdd:cd11970     5 AVKALFDYKAQREDELTFTKNAIIQNVEK--QEGGWWRGDYGGKKQlWFPSNYVE 57

Src homology 3 domain of Abl Interactor 2; Abi2 is highly expressed in the brain and eye. It regulates actin cytoskeletal reorganization at adherens junctions and dendritic spines, which is important in cell morphogenesis, migration, and cognitive function. Mice deficient with Abi2 show defects in orientation and migration of lens fibers, neuronal migration, dendritic spine morphology, as well as deficits in learning and memory. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212905 [Multi-domain] Cd Length: 61 Bit Score: 42.30 E-value: 6.25e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  931 LDEYVALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11972     2 LEKVVAIYDYTKDKEDELSFQEGAIIYVIKKNDDgWYEGVMNGVTGLFPGNYVE 55

Third Src Homology 3 domain (SH3C) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CIN85. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212990 [Multi-domain] Cd Length: 56 Bit Score: 42.19 E-value: 6.35e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  937 LYTYESPESGDLTFSAEDVVLVTEKE---GEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd12057     5 LFPYEAQNEDELTIKEGDIVTLISKDcidAGWWEGELNGRRGVFPDNFVK 54

Src Homology 3 domain of Insulin Receptor tyrosine kinase Substrate p53, Brain-specific Angiogenesis Inhibitor 1-Associated Protein 2 (BAIAP2)-Like proteins, and similar proteins; Proteins in this family include IRSp53, BAIAP2L1, BAIAP2L2, and similar proteins. They all contain an Inverse-Bin/Amphiphysin/Rvs (I-BAR) or IMD domain in addition to the SH3 domain. IRSp53, also known as BAIAP2, is a scaffolding protein that takes part in many signaling pathways including Cdc42-induced filopodia formation, Rac-mediated lamellipodia extension, and spine morphogenesis. IRSp53 exists as multiple splicing variants that differ mainly at the C-termini. BAIAP2L1, also called IRTKS (Insulin Receptor Tyrosine Kinase Substrate), serves as a substrate for the insulin receptor and binds the small GTPase Rac. It plays a role in regulating the actin cytoskeleton and colocalizes with F-actin, cortactin, VASP, and vinculin. IRSp53 and IRTKS also mediate the recruitment of effector proteins Tir and EspFu, which regulate host cell actin reorganization, to bacterial attachment sites. BAIAP2L2 co-localizes with clathrin plaques but its function has not been determined. The SH3 domains of IRSp53 and IRTKS have been shown to bind the proline-rich C-terminus of EspFu. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212713 [Multi-domain] Cd Length: 57 Bit Score: 41.92 E-value: 6.58e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDESTVREtGWLYGSY--SGNRGWFPESYAE 804
Cdd:cd11779     4 KALYPHAAGGETQLSFEEGDVITLLGPEPRD-GWHYGENerSGRRGWFPIAYTE 56

First Src Homology 3 domain of SH3 domain containing ring finger 2; SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal RING finger domain and three SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212862 Cd Length: 54 Bit Score: 42.23 E-value: 6.60e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIItVLEKQ--ENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11929     2 RAKALCNYRGHNPGDLKFNKGDVI-LLRRQldENWYLGEINGVSGIFPASSVEV 54

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and scaffold proteins and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212764 [Multi-domain] Cd Length: 54 Bit Score: 41.85 E-value: 6.74e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLEK--QENWWYGELKEKRGWFPCSHV 903
Cdd:cd11830     2 AKARYDFCARDMRELSLKEGDVVKIYNKkgQQGWWRGEINGRIGWFPSTYV 52

Src Homology 3 domain of Class A and B Dedicator of Cytokinesis proteins; DOCK proteins are atypical guanine nucleotide exchange factors (GEFs) that lack the conventional Dbl homology (DH) domain. They are divided into four classes (A-D) based on sequence similarity and domain architecture: class A includes Dock1, 2 and 5; class B includes Dock3 and 4; class C includes Dock6, 7, and 8; and class D includes Dock9, 10 and 11. All DOCKs contain two homology domains: the DHR-1 (Dock homology region-1), also called CZH1 (CED-5, Dock180, and MBC-zizimin homology 1), and DHR-2 (also called CZH2 or Docker). The DHR-1 domain binds phosphatidylinositol-3,4,5-triphosphate while DHR-2 contains the catalytic activity for Rac and/or Cdc42. This subfamily includes only Class A and B DOCKs, which also contain an SH3 domain at the N-terminal region and a PxxP motif at the C-terminus. Class A/B DOCKs are mostly specific GEFs for Rac, except Dock4 which activates the Ras family GTPase Rap1, probably indirectly through interaction with Rap regulatory proteins. The SH3 domain of class A/B DOCKs have been shown to bind Elmo, a scaffold protein that promotes GEF activity of DOCKs by releasing DHR-2 autoinhibition by the intramolecular SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212805 [Multi-domain] Cd Length: 56 Bit Score: 41.80 E-value: 7.06e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLEKQENWWYGEL---KEKRGWFPCSHV 903
Cdd:cd11872     2 GVAIYNFQGDGEHQLSLQVGDTVQILEECEGWYRGFSlrnKSLKGIFPKSYV 53

C2 domain present in Smad ubiquitination-related factor (Smurf)-like proteins; A single C2 domain is found in Smurf proteins, C2-WW-HECT-domain E3s, which play an important role in the downregulation of the TGF-beta signaling pathway. Smurf proteins also regulate cell shape, motility, and polarity by degrading small guanosine triphosphatases (GTPases). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have type-II topology.

Pssm-ID: 176028 [Multi-domain] Cd Length: 123 Bit Score: 43.83 E-value: 7.15e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1534 PYCELTM-GAQCYTSRHQPDTLNPKWSFNCQFFIKDlyQDVLCLTVFERDQFSPDD--FLGRTEVPVATIkkdQDGKGPL 1610
Cdd:cd08382    23 PFAVITVdGGQTHSTDVAKKTLDPKWNEHFDLTVGP--SSIITIQVFDQKKFKKKDqgFLGCVRIRANAV---LPLKDTG 97


                  ....*..
gi 688602146 1611 VRRLLLH 1617
Cdd:cd08382    98 YQRLDLR 104

Third (or C-terminal) Src Homology 3 domain of Vinexin, also called Sorbin and SH3 domain containing 3 (Sorbs3); Vinexin is also called Sorbs3, SH3P3, and SH3-containing adapter molecule 1 (SCAM-1). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. Vinexin was first identified as a vinculin binding protein; it is co-localized with vinculin at cell-ECM and cell-cell adhesion sites. There are several splice variants of vinexin: alpha, which contains the SoHo and three SH3 domains and displays tissue-specific expression; and beta, which contains only the three SH3 domains and is widely expressed. Vinexin alpha stimulates the accumulation of F-actin at focal contact sites. Vinexin also promotes keratinocyte migration and wound healing. The SH3 domains of vinexin have been reported to bind a number of ligands including vinculin, WAVE2, DLG5, Abl, and Cbl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212851 [Multi-domain] Cd Length: 58 Bit Score: 42.25 E-value: 7.23e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKG--EVAGVTGLFPTNYV 1125
Cdd:cd11918     6 AVYQYRPQNEDELELREGDRVDVMQQCDDGWFVGvsRRTQKFGTFPGNYV 55

Third (or C-terminal) Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the third SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212714 [Multi-domain] Cd Length: 55 Bit Score: 41.90 E-value: 7.35e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSY--SGNRGWFPESYAER 805
Cdd:cd11780     2 YRALYSYTPQNEDELELREGDIVYVMEKC--DDGWFVGTSerTGLFGTFPGNYVAR 55

C2 domain present in cytosolic PhosphoLipase A2 (cPLA2); A single copy of the C2 domain is present in cPLA2 which releases arachidonic acid from membranes initiating the biosynthesis of potent inflammatory mediators such as prostaglandins, leukotrienes, and platelet-activating factor. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members of this cd have a type-II topology.

Pssm-ID: 176001 [Multi-domain] Cd Length: 119 Bit Score: 43.79 E-value: 7.59e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1512 RLLVTVLEATELKPCKPNGKSNPYCEL---TMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQFsPDD 1588
Cdd:cd04036     1 LLTVRVLRATNITKGDLLSTPDCYVELwlpTASDEKKRTKTIKNSINPVWNETFEFRIQSQVKNVLELTVMDEDYV-MDD 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 688602146 1589 FLGRTEVPVATIKKDQdgkgPLVRRLLLHEVPTGEVKVRLDLQL 1632
Cdd:cd04036    80 HLGTVLFDVSKLKLGE----KVRVTFSLNPQGKEELEVEFLLEL 119

Src homology 3 domain of the Rho guanine nucleotide exchange factor, ephexin-1 (also called NGEF or ARHGEF27); Ephexin-1, also called NGEF (neuronal GEF) or ARHGEF27, activates RhoA, Tac1, and Cdc42 by exchanging bound GDP for free GTP. It is expressed mainly in the brain in a region associated with movement control. It regulates the stability of postsynaptic acetylcholine receptor (AChR) clusters and thus, plays a critical role in the maturation and neurotransmission of neuromuscular junctions. Ephexin-1 directly interacts with the ephrin receptor EphA4 and their coexpression enhances the ability of ephexin-1 to activate RhoA. It is required for normal axon growth and EphA-induced growth cone collapse. Ephexin-1 contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and SH3 domains. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212872 [Multi-domain] Cd Length: 55 Bit Score: 41.85 E-value: 7.59e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  755 LYPFTARNSDELTLEADCFIQVDESTvrETGWLYGS--YSGNRGWFPESYAE 804
Cdd:cd11939     5 VHPYVSQEPDELSLELADVLNILDKT--DDGWIFGErlHDQERGWFPSSVVE 54

C2 domain first repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-II topology.

Pssm-ID: 176009 [Multi-domain] Cd Length: 124 Bit Score: 44.08 E-value: 7.80e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1510 IGRLLVTVLEATELK-PCKPNGKSNPYCELTMGAQ--CYTSRHQPDTLNPKWSfNCQFFIKDLYQDVLCLTVFERDQFSP 1586
Cdd:cd04044     1 IGVLAVTIKSARGLKgSDIIGGTVDPYVTFSISNRreLARTKVKKDTSNPVWN-ETKYILVNSLTEPLNLTVYDFNDKRK 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 688602146 1587 DDFLGRTEVPVATIKKD--QDGkgpLVRRLLLHEVPTGEVK 1625
Cdd:cd04044    80 DKLIGTAEFDLSSLLQNpeQEN---LTKNLLRNGKPVGELN 117

Src Homology 3 domain of Myosin XV; This subfamily is composed of proteins with similarity to Myosin XVa. Myosin XVa is an unconventional myosin that is critical for the normal growth of mechanosensory stereocilia of inner ear hair cells. Mutations in the myosin XVa gene are associated with nonsyndromic hearing loss. Myosin XVa contains a unique N-terminal extension followed by a motor domain, light chain-binding IQ motifs, and a tail consisting of a pair of MyTH4-FERM tandems separated by a SH3 domain, and a PDZ domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212817 [Multi-domain] Cd Length: 56 Bit Score: 41.93 E-value: 7.87e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGE----WWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11884     3 VAVRAYITRDQTLLSFHKGDVIKLLPKEGPldpgWLFGTLDGRSGAFPKEYVQP 56

First Src Homology 3 domain of Vinexin, also called Sorbin and SH3 domain containing 3 (Sorbs3); Vinexin is also called Sorbs3, SH3P3, and SH3-containing adapter molecule 1 (SCAM-1). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. Vinexin was first identified as a vinculin binding protein; it is co-localized with vinculin at cell-ECM and cell-cell adhesion sites. There are several splice variants of vinexin: alpha, which contains the SoHo and three SH3 domains and displays tissue-specific expression; and beta, which contains only the three SH3 domains and is widely expressed. Vinexin alpha stimulates the accumulation of F-actin at focal contact sites. Vinexin also promotes keratinocyte migration and wound healing. The SH3 domains of vinexin have been reported to bind a number of ligands including vinculin, WAVE2, DLG5, Abl, and Cbl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212854 Cd Length: 55 Bit Score: 41.83 E-value: 8.18e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11921     5 LKFDFQAQSPKELTLQKGDIVYIHKEVDKNWLEGEHHGRVGIFPANYVEV 54

Third Src Homology 3 domain of Nck adaptor proteins; This group contains the third SH3 domain of Nck, the first SH3 domain of Caenorhabditis elegans Ced-2 (Cell death abnormality protein 2), and similar domains. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The third SH3 domain of Nck appears to prefer ligands with a PxAPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. Ced-2 is a cell corpse engulfment protein that interacts with Ced-5 in a pathway that regulates the activation of Ced-10, a Rac small GTPase.

Pssm-ID: 212701 [Multi-domain] Cd Length: 56 Bit Score: 41.91 E-value: 8.34e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEK---EGEWW--RGCIGdQTGLFPSNYVK 983
Cdd:cd11767     3 VALYPFTGENDEELSFEKGERLEIIEKpedDPDWWkaRNALG-TTGLVPRNYVE 55

C2 domain second repeat present in Synaptotagmin; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. There are several classes of Synaptotagmins. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 175975 [Multi-domain] Cd Length: 134 Bit Score: 44.11 E-value: 8.77e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKPCKPNGKSNPYCELTMGAQ-----CYTSRHQPDTLNPKWsfNCQFFIK----DLYQDVLCLTVFER 1581
Cdd:cd00276    14 ERLTVVVLKARNLPPSDGKGLSDPYVKVSLLQGgkklkKKKTSVKKGTLNPVF--NEAFSFDvpaeQLEEVSLVITVVDK 91

                          90
                  ....*....|....
gi 688602146 1582 DQFSPDDFLGRTEV 1595
Cdd:cd00276    92 DSVGRNEVIGQVVL 105

Second or C-terminal Src homology 3 domain of the p47phox subunit of NADPH oxidase, also called Neutrophil Cytosolic Factor 1; p47phox, or NCF1, is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p47phox is required for activation of NADH oxidase and plays a role in translocation. It contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), a polybasic/autoinhibitory region, and a C-terminal proline-rich region (PRR). This model characterizes the second SH3 domain (or C-SH3) of p47phox. In its inactive state, the tandem SH3 domains interact intramolecularly with the autoinhibitory region; upon activation, the tandem SH3 domains are exposed through a conformational change, resulting in their binding to the PRR of p22phox and the activation of NADPH oxidase. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212955 [Multi-domain] Cd Length: 53 Bit Score: 41.75 E-value: 8.82e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWW---KGEvagVTGLFPTNYVK 1126
Cdd:cd12022     3 ITIKAYTAVEEDELTLLEGEAIEVIHKLLDGWWvvrKGE---VTGYFPSMYLQ 52

Src Homology 3 domain of Bbc1 and similar domains; This subfamily is composed of Saccharomyces cerevisiae Bbc1p, also called Mti1p (Myosin tail region-interacting protein), and similar proteins. Bbc1p interacts with and regulates type I myosins in yeast, Myo3p and Myo5p, which are involved in actin cytoskeletal reorganization. It also binds and inhibits Las17, a WASp family protein that functions as an activator of the Arp2/3 complex. Bbc1p contains an N-terminal SH3 domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212820 [Multi-domain] Cd Length: 60 Bit Score: 41.94 E-value: 9.06e-05

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 688602146  750 TTYRALYPFTARNSDELTLEADCFIQVDEstVRETGWLYGSY---SGNR--GWFPESYAER 805
Cdd:cd11887     2 FKVKALYPYESDHEDDLNFDVGQLITVTE--EEDADWYFGEYvdsNGNTkeGIFPKNFVEV 60

First Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212861 Cd Length: 54 Bit Score: 41.83 E-value: 9.06e-05

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHV 903
Cdd:cd11928     5 ALYSYEGKEPGDLKFNKGDIIILRRKvDENWYHGELNGCHGFLPASYI 52

Third N-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin and key regulatory proteins of the actin cytoskeleton. It plays an important role in regulating cell junction configuration. The four N-terminal SH3 domains of DNMBP binds the GTPase dynamin, which plays an important role in the fission of endocytic vesicles. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212730 Cd Length: 51 Bit Score: 41.57 E-value: 9.38e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQENWWY-GELKEKRGWFPCSHV 903
Cdd:cd11796     1 QARVLQDLSAQLDEELDLREGDVVTITGILDKGWFrGELNGRRGIFPEGFV 51

First Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis. Together with other proteins, it induces membrane scission in yeast. Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This model represents the first C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212845 [Multi-domain] Cd Length: 55 Bit Score: 41.44 E-value: 9.44e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWW----KGevAGVTGLFPTNYVKM 1127
Cdd:cd11912     4 VLYDYTASGDDEVSISEGEEVTVLEPDDGSGWtkvrNG--SGEEGLVPTSYIEI 55

Fifth Src homology 3 domain (or SH3E) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212774 [Multi-domain] Cd Length: 53 Bit Score: 41.63 E-value: 9.65e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  753 RALYPFTARNSDELTLEADCFIQV---DESTvretgWLYGSYSGNRGWFPESYAE 804
Cdd:cd11840     3 IALFPYTAQNEDELSFQKGDIINVlskDDPD-----WWRGELNGQTGLFPSNYVE 52

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212700 [Multi-domain] Cd Length: 53 Bit Score: 41.48 E-value: 1.01e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146 1009 PATTPEQLSLTPGQLIVVLHKNSNSWWLGELQARgkkrkKGWFQSSNV 1056
Cdd:cd11766     9 EAQREDELSLRKGDRVLVLEKSSDGWWRGECNGQ-----VGWFPSNYV 51

C-terminal Src Homology 3 domain of the Nebulin family of proteins; Nebulin family proteins contain multiple nebulin repeats, and may contain an N-terminal LIM domain and/or a C-terminal SH3 domain. They have molecular weights ranging from 34 to 900 kD, depending on the number of nebulin repeats, and they all bind actin. They are involved in the regulation of actin filament architecture and function as stabilizers and scaffolds for cytoskeletal structures with which they associate, such as long actin filaments or focal adhesions. Nebulin family proteins that contain a C-terminal SH3 domain include the giant filamentous protein nebulin, nebulette, Lasp1, and Lasp2. Lasp2, also called LIM-nebulette, is an alternatively spliced variant of nebulette. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212723 [Multi-domain] Cd Length: 55 Bit Score: 41.53 E-value: 1.03e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  751 TYRALYPFTARNSDELTL-EADCFIQVdesTVRETGWLYG--SYSGNRGWFPESYAE 804
Cdd:cd11789     1 RYRAMYDYAAADDDEVSFqEGDVIINV---EIIDDGWMEGtvQRTGQSGMLPANYVE 54

Second Src homology 3 domain (or SH3B) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212923 [Multi-domain] Cd Length: 52 Bit Score: 41.57 E-value: 1.04e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDEstvRETGWLYGSYSGNRGWFPESY 802
Cdd:cd11990     3 QALCSWTAKKDNHLNFSKNDIITVLE---QQENWWFGEVHGGRGWFPKSY 49

First Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212695 [Multi-domain] Cd Length: 57 Bit Score: 41.58 E-value: 1.05e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  749 LTTYRALYPFTARNSDELTLEADCFIQVDESTVREtGWLYG-SYSGNRGWFPESYAE 804
Cdd:cd11761     1 PVTCKVLYSYEAQRPDELTITEGEELEVIEDGDGD-GWVKArNKSGEVGYVPENYLQ 56

Src homology 3 domain of High osmolarity signaling protein Sho1p; Sho1p (or Sho1), also called SSU81 (Suppressor of SUA8-1 mutation), is a yeast membrane protein that regulates adaptation to high salt conditions by activating the HOG (high-osmolarity glycerol) pathway. High salt concentrations lead to the localization to the membrane of the MAPKK Pbs2, which is then activated by the MAPKK Ste11 and in turn, activates the MAPK Hog1. Pbs2 is localized to the membrane though the interaction of its PxxP motif with the SH3 domain of Sho1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212789 [Multi-domain] Cd Length: 55 Bit Score: 41.64 E-value: 1.05e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYE-SPES-GDLTFSAEDVVLVTEKEGEWWRGCIGD-QTGLFPSNYV 982
Cdd:cd11855     4 ALYPYDaSPDDpNELSFEKGEILEVSDTSGKWWQARKSNgETGICPSNYL 53

Second Src homology 3 domain of Tyrosine kinase substrate with five SH3 domains; Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains. This model characterizes the second SH3 domain of Tks5. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213010 Cd Length: 54 Bit Score: 41.56 E-value: 1.06e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTVRetGWLYGSYSGNRGWFPESYAER 805
Cdd:cd12077     3 YVTVQPYTSQGKDEIGFEKGVTVEVIQKNLE--GWWYIRYLGKEGWAPASYLKK 54

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the peroxisomal membrane, contains two transmembrane regions and a C-terminal SH3 domain. It binds to the peroxisomal targeting type I (PTS1) receptor Pex5p and the docking factor Pex14p through its SH3 domain. It is essential for both PTS1 and PTS2 protein import pathways into the peroxisomal matrix. Pex13p binds Pex14p, which contains a PxxP motif, in a classical fashion to the proline-rich ligand binding site of its SH3 domain. It binds the WxxxF/Y motif of Pex5p in a novel site that does not compete with Pex14p binding. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212705 [Multi-domain] Cd Length: 60 Bit Score: 41.49 E-value: 1.07e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  753 RALYPFTARNSD-ELTLEADCFIQV---DESTVRETGWLYG-SYSGNRGWFPESYAE 804
Cdd:cd11771     3 RALYDFTPENPEmELSLKKGDIVAVlskTDPLGRDSEWWKGrTRDGRIGWFPSNYVE 59

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212909 [Multi-domain] Cd Length: 54 Bit Score: 41.47 E-value: 1.11e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE--WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11976     4 ARYDFCARDRSELSLKEGDIIKILNKKGQqgWWRGEIYGRVGWFPANYVE 53

Second Src homology 3 domain (or SH3B) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212922 [Multi-domain] Cd Length: 52 Bit Score: 41.24 E-value: 1.14e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDEstvRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11989     3 QALYPWRAKKDNHLNFNKNDVITVLE---QQDMWWFGEVQGQKGWFPKSYVK 51

Afadin- and alpha -actinin-Binding; This family is found in mammals where it is localized at cell-cell adherens junctions, and in Sch. pombe and other fungi where it anchors spindle-pole bodies to spindle microtubules. It is a coiled-coil structure, and in pombe, it is required for anchoring the minus end of spindle microtubules to the centrosome equivalent, the spindle-pole body. The name ADIP derives from the family being composed of Afadin- and alpha -Actinin-Binding Proteins localized at Cell-Cell Adherens Junctions.

Pssm-ID: 463295 [Multi-domain] Cd Length: 151 Bit Score: 44.23 E-value: 1.15e-04

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   457 LQTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKrqgqwaelelinqrrdvcitdinsLQLQFDEMQR 536
Cdd:pfam11559   64 LEAEIERLQSKIERLKTQLEDLERELALLQAKERQLEKKLKTLEQK------------------------LKNEKEELQR 119

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 688602146   537 QLNQLgpekqrladrlvhftQNISSPLINDVKQsvceKDRSCRKLKEQL 585
Cdd:pfam11559  120 LKNAL---------------QQIKTQFAHEVKK----RDREIEKLKERL 149

Second Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the second SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212716 [Multi-domain] Cd Length: 53 Bit Score: 41.18 E-value: 1.17e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11782     1 EARAKYNFNADTGVELSFRKGDVITLTRRvDENWYEGRIGGRQGIFPVSYVQ 52

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 394975 [Multi-domain] Cd Length: 47 Bit Score: 41.04 E-value: 1.18e-04

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 688602146  1009 PATTPEQLSLTPGQLIVVLHKNSNSWWLGELqargKKRKKGWF 1051
Cdd:pfam00018    7 TAQEPDELSFKKGDIIIVLEKSEDGWWKGRN----KGGKEGLI 45

C-terminal Src Homology 3 domain of LIM and SH3 domain protein 1; Lasp1 is a cytoplasmic protein that binds focal adhesion proteins and is involved in cell signaling, migration, and proliferation. It is overexpressed in several cancer cells including breast, ovarian, bladder, and liver. In cancer cells, it can be found in the nucleus; its degree of nuclear localization correlates with tumor size and poor prognosis. Lasp1 is a 36kD protein containing an N-terminal LIM domain, two nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212867 [Multi-domain] Cd Length: 59 Bit Score: 41.52 E-value: 1.28e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  752 YRALYPFTARNSDELTL-EADCFIQVDEStvrETGWLYGSY--SGNRGWFPESYAE 804
Cdd:cd11934     5 YRAVYDYNAADEDEVSFqDGDTIVNVQQI---DDGWMYGTVerTGDTGMLPANYVE 57

C-terminal Src Homology 3 domain of the p67phox subunit of NADPH oxidase and similar proteins; This subfamily is composed of p67phox, NADPH oxidase activator 1 (Noxa1), and similar proteins. p67phox, also called Neutrophil cytosol factor 2 (NCF-2), and Noxa1 are homologs and are the cytosolic subunits of the phagocytic (Nox2) and nonphagocytic (Nox1) NADPH oxidase complexes, respectively. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox and Noxa1 play regulatory roles. p67phox contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. Noxa1 has a similar domain architecture except it is lacking the N-terminal SH3 domain. The TPR domain of both binds activated GTP-bound Rac, while the C-terminal SH3 domain of p67phox and Noxa1 binds the polyproline motif found at the C-terminus of p47phox and Noxo1, respectively. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212803 [Multi-domain] Cd Length: 53 Bit Score: 40.98 E-value: 1.35e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLV-TEKEGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11870     3 VALHRYEAQGPEDLGFREGDTIDVlSEVNEAWLEGHSDGRVGIFPKCFVVP 53

C2 domain third repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

Pssm-ID: 176010 [Multi-domain] Cd Length: 120 Bit Score: 42.96 E-value: 1.40e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKPCKPNGKSNPYCELTM-GAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQdVLCLTVFERDQFSPDDF 1589
Cdd:cd04045     1 GVLRLHIRKANDLKNLEGVGKIDPYVRVLVnGIVKGRTVTISNTLNPVWDEVLYVPVTSPNQ-KITLEVMDYEKVGKDRS 79

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 688602146 1590 LGRTEVPVAT-IKKDQDGK--------GPLVRRLLLHEV 1619
Cdd:cd04045    80 LGSVEINVSDlIKKNEDGKyveyddeeERLKRLLSLKGV 118

Src homology 3 domain of Apoptosis Stimulating of p53 proteins (ASPP); The ASPP family of proteins bind to important regulators of apoptosis (p53, Bcl-2, and RelA) and cell growth (APCL, PP1). They share similarity at their C-termini, where they harbor a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain. Vertebrates contain three members of the family: ASPP1, ASPP2, and iASPP. ASPP1 and ASPP2 activate the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73), while iASPP is an oncoprotein that specifically inhibits p53-induced apoptosis. The expression of ASPP proteins is altered in tumors; ASPP1 and ASPP2 are downregulated whereas iASPP is upregulated is some cancer types. ASPP proteins also bind and regulate protein phosphatase 1 (PP1), and this binding is competitive with p53 binding. The SH3 domain and the ANK repeats of ASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212741 [Multi-domain] Cd Length: 57 Bit Score: 41.21 E-value: 1.43e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVT----EKEGEWWRGCIGDQTGLFPSNY 981
Cdd:cd11807     5 ALFDYEAENGDELSFREGDELTVLrkgdDDETEWWWARLNDKEGYVPRNL 54

Src homology 3 domain of Slit-Robo GTPase Activating Protein 4; srGAP4, also called ARHGAP4, is highly expressed in hematopoietic cells and may play a role in lymphocyte differentiation. It is able to stimulate the GTPase activity of Rac1, Cdc42, and RhoA. In the nervous system, srGAP4 has been detected in differentiating neurites and may be involved in axon and dendritic growth. srGAPs are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212889 [Multi-domain] Cd Length: 55 Bit Score: 40.98 E-value: 1.44e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11956     3 EAVACFDYTGRTAQELSFKRGDVLLLHSKaSSDWWRGEHNGMRGLIPHKYISV 55

C-terminal (or second) Src Homology 3 domain of the p67phox subunit of NADPH oxidase; p67phox, also called Neutrophil cytosol factor 2 (NCF-2), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox plays a regulatory role and contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. It binds, via its C-terminal SH3 domain, to a proline-rich region of p47phox and upon activation, this complex assembles with flavocytochrome b558, the Nox2-p22phox heterodimer. Concurrently, RacGTP translocates to the membrane and interacts with the TPR domain of p67phox, which leads to the activation of NADPH oxidase. The PB1 domain of p67phox binds to its partner PB1 domain in p40phox, and this facilitates the assembly of p47phox-p67phox at the membrane. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212979 [Multi-domain] Cd Length: 53 Bit Score: 40.94 E-value: 1.52e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHV 903
Cdd:cd12046     1 QVVALFSYEASQPEDLEFQKGDVILVLSKvNEDWLEGQCKGKIGIFPSAFV 51

Src homology 3 domain of Abl Interactor proteins; Abl interactor (Abi) proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. They localize to sites of actin polymerization in epithelial adherens junction and immune synapses, as well as to the leading edge of lamellipodia. Vertebrates contain two Abi proteins, Abi1 and Abi2. Abi1 displays a wide expression pattern while Abi2 is highly expressed in the eye and brain. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212760 [Multi-domain] Cd Length: 52 Bit Score: 40.77 E-value: 1.55e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11826     3 VALYDYTADKDDELSFQEGDIIYVTKKN--DDGWYEGVLNGVTGLFPGNYVE 52

Src homology 3 domain of Endophilin-B2; Endophilin-B2, also called SH3GLB2 (SH3-domain GRB2-like endophilin B2), is a cytoplasmic protein that interacts with the apoptosis inducer Bax. It is overexpressed in prostate cancer metastasis and has been identified as a cancer antigen with potential utility in immunotherapy. Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. Endophilin-B2 forms homo- and heterodimers (with endophilin-B1) through its BAR domain. The related protein endophilin-B1 interacts with amphiphysin 1 and dynamin 1 through its SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212877 Cd Length: 55 Bit Score: 41.13 E-value: 1.58e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITV--LNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd11944     4 VLYDYEAADSSELALLADELITVysLPGMDPDWLIGERGNQKGKVPVTYLEL 55

Src homology 3 domain of Phospholipase C (PLC) gamma 2; PLCgamma2 is primarily expressed in haematopoietic cells, specifically in B cells. It is activated by tyrosine phosphorylation by B cell receptor (BCR) kinases and is recruited to the plasma membrane where its substrate is located. It is required in pre-BCR signaling and in the maturation of B cells. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212902 Cd Length: 55 Bit Score: 40.98 E-value: 1.59e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVL-VTEKEGEWWRGCIGDQTG-LFPSNYVK 983
Cdd:cd11969     4 ALYDYRAKRSDELSFCKGALIHnVSKETGGWWKGDYGGKVQhYFPSNYVE 53

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing (Stac) proteins; Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. This model represents the first C-terminal SH3 domain of Stac1 and Stac3, and the single C-terminal SH3 domain of Stac2. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212767 [Multi-domain] Cd Length: 53 Bit Score: 40.95 E-value: 1.61e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLE-KQENWWYGELKEKRGWFPCSHV 903
Cdd:cd11833     3 VALYKFKPQENEDLEMRPGDKITLLDdSNEDWWKGKIEDRVGFFPANFV 51

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If (MyoIf) are nonmuscle, unconventional, long tailed, class I myosins containing an N-terminal motor domain and a myosin tail with TH1, TH2, and SH3 domains. MyoIe interacts with the endocytic proteins, dynamin and synaptojanin-1, through its SH3 domain; it may play a role in clathrin-dependent endocytosis. In the kidney, MyoIe is critical for podocyte function and normal glomerular filtration. Mutations in MyoIe is associated with focal segmental glomerulosclerosis, a disease characterized by massive proteinuria and progression to end-stage kidney disease. MyoIf is predominantly expressed in the immune system; it plays a role in immune cell motility and innate immunity. Mutations in MyoIf may be associated with the loss of hearing. The MyoIf gene has also been found to be fused to the MLL (Mixed lineage leukemia) gene in infant acute myeloid leukemias (AML). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212761 [Multi-domain] Cd Length: 53 Bit Score: 40.86 E-value: 1.66e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  753 RALYPFTARNSDELTLEADCFIQV---DEStvretGWLYGSYSGNRGWFPESYAER 805
Cdd:cd11827     3 KALYAYDAQDTDELSFNEGDIIEIlkeDPS-----GWWTGRLRGKEGLFPGNYVEK 53

Src homology 3 domain of Growth Arrest Specific protein 7; GAS7 is mainly expressed in the brain and is required for neurite outgrowth. It may also play a role in the protection and migration of embryonic stem cells. Treatment-related acute myeloid leukemia (AML) has been reported resulting from mixed-lineage leukemia (MLL)-GAS7 translocations as a complication of primary cancer treatment. GAS7 contains an N-terminal SH3 domain, followed by a WW domain, and a central F-BAR domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212763 [Multi-domain] Cd Length: 52 Bit Score: 40.96 E-value: 1.72e-04

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 688602146  869 LGFCKDDIITVLEKQEN-WWYGELKEKRGWFPCSHV 903
Cdd:cd11829    17 LSFEAGELIRVLQAPDGgWWEGEKDGLRGWFPASYV 52

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor; ASEF, also called ARHGEF4, exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli). GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF can activate Rac1 or Cdc42. Truncated ASEF, which is found in colorectal cancers, is constitutively active and has been shown to promote angiogenesis and cancer cell migration. ASEF contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212906 [Multi-domain] Cd Length: 73 Bit Score: 41.54 E-value: 1.72e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLE-KQENWWYGELKEKRGWFPCSHV 903
Cdd:cd11973    20 AEALWDHVTMDDQELGFKAGDVIEVMDaTNKEWWWGRVLDSEGWFPASFV 69

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; N-terminal SH3 domain of the uncharacterized protein SH3 domain-containing protein 21, and similar uncharacterized domains, it belongs to the CD2AP-like_3 subfamily of proteins. The CD2AP-like_3 subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213018 [Multi-domain] Cd Length: 55 Bit Score: 40.91 E-value: 1.75e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  937 LYTYESPESGDLTFSAEDVVLVTEKEGE---WWRGCIGDQTGLFPSNYVKP 984
Cdd:cd12142     5 LFDYNPVAPDELALKKGDVIEVISKETEdegWWEGELNGRRGFFPDNFVMP 55

Third Src homology 3 domain (or SH3C) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212924 Cd Length: 52 Bit Score: 40.74 E-value: 1.81e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLEKQENWWYGELKEKRGWFPCSHV 903
Cdd:cd11991     3 VAMYTYESNEQGDLTFQQGDVILVTKKDGDWWTGTVGDKTGVFPSNYV 50

First Src homology 3 domain (or SH3A) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212920 [Multi-domain] Cd Length: 55 Bit Score: 40.75 E-value: 1.97e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKE-GE--WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11987     2 YRALYPFEARSHDEITIQPGDIVMVDESQtGEpgWLGGELKGKTGWFPANYAE 54

First Src Homology 3 domain (SH3A) of CD2-associated protein and similar proteins; This subfamily is composed of the first SH3 domain (SH3A) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3A of both proteins bind to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic domain of the cell adhesion protein CD2. CIN85 SH3A binds to internal proline-rich motifs within the proline-rich region; this intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. CIN85 SH3A has also been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212806 [Multi-domain] Cd Length: 53 Bit Score: 40.71 E-value: 2.07e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIIT-VLEKQENWWYGELKEKRGWFP 899
Cdd:cd11873     2 VIVEFDYDAEEPDELTLKVGDIITnVKKMEEGWWEGTLNGKRGMFP 47

First Src Homology 3 domain of Bud emergence protein 1 and similar domains; Members of this subfamily bear similarity to Saccharomyces cerevisiae Bem1p, containing two Src Homology 3 (SH3) domains at the N-terminus, a central PX domain, and a C-terminal PB1 domain. Bem1p is a scaffolding protein that is critical for proper Cdc42p activation during bud formation in yeast. During budding and mating, Bem1p migrates to the plasma membrane where it can serve as an adaptor for Cdc42p and some other proteins. Bem1p also functions as an effector of the G1 cyclin Cln3p and the cyclin-dependent kinase Cdc28p in promoting vacuolar fusion. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212811 [Multi-domain] Cd Length: 54 Bit Score: 40.73 E-value: 2.07e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1076 VI-AMYDYKAANKDEMSFQKGQLITVLNKDNPD-WWKGE--VAGVTGLFPTNY 1124
Cdd:cd11878     1 VIrALYDYRAQTPGELSFSKGDFFHVIGEEDQGeWYEATnpVTGKRGLVPKSY 53

Family of unknown function (DUF5401); This is a family of unknown function found in Chromadorea.

Pssm-ID: 375164 [Multi-domain] Cd Length: 722 Bit Score: 46.27 E-value: 2.07e-04

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   451 KSKRVELQTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRqgqwaELELINQRRdvcitdinsLQLQ 530
Cdd:pfam17380  308 KAREVERRRKLEEAEKARQAEMDRQAAIYAEQERMAMERERELERIRQEERKR-----ELERIRQEE---------IAME 373

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   531 FDEMqRQLNQLGPEKQRLADRlvhftqnISSPLINDVKQSVCEKDRScRKLKEQLDVLER----ETTAKLSQM----EQY 602
Cdd:pfam17380  374 ISRM-RELERLQMERQQKNER-------VRQELEAARKVKILEEERQ-RKIQQQKVEMEQiraeQEEARQREVrrleEER 444

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   603 NKEIKELRQKQSQQQDVLEQLRRVRSD-KLKELQRHRKEEEERKRKKEEEAARQAQLEQERLEQEEAERQRKL----AQE 677
Cdd:pfam17380  445 AREMERVRLEEQERQQQVERLRQQEEErKRKKLELEKEKRDRKRAEEQRRKILEKELEERKQAMIEEERKRKLlekeMEE 524

                          250
                   ....*....|..
gi 688602146   678 REAKLREEQQRQ 689
Cdd:pfam17380  525 RQKAIYEEERRR 536

Fourth Src homology 3 domain (or SH3D) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fourth SH3 domain (or SH3D) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212927 Cd Length: 59 Bit Score: 40.69 E-value: 2.16e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  853 SQAVALCewSAKTDSHLGFCKDDIITVLEKQEN-WWYGEL-----KEKRGWFPCSHV 903
Cdd:cd11994     2 AQVTTAY--VASGVEQLSLSPGQLILILKKNSSgWWLGELqargkKRQKGWFPASHV 56

Src Homology 3 domain of Sorting Nexin 33; SNX33 interacts with Wiskott-Aldrich syndrome protein (WASP) and plays a role in the maintenance of cell shape and cell cycle progression. It modulates the shedding and endocytosis of cellular prion protein (PrP(c)) and amyloid precursor protein (APP). SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX33 also contains BAR and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212829 [Multi-domain] Cd Length: 55 Bit Score: 40.71 E-value: 2.17e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  753 RALYPFTARNSDELTLEADCFIQV-DESTVreTGWLYGSYS-GNRGWFPESYAE 804
Cdd:cd11896     3 RALYSFQSENKEEINIQENEELVIfSENSL--DGWLQGQNSrGETGLFPASYVE 54

Second Src homology 3 domain of Tyrosine kinase substrate with five SH3 domains; Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains. This model characterizes the second SH3 domain of Tks5. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213010 Cd Length: 54 Bit Score: 40.40 E-value: 2.22e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12077     4 VTVQPYTSQGKDEIGFEKGVTVEVIQKNLEGWWYIRYLGKEGWAPASYLK 53

Third (or C-terminal) Src Homology 3 domain of Sorbin and SH3 domain containing 1 (Sorbs1), also called ponsin; Sorbs1 is also called ponsin, SH3P12, or CAP (c-Cbl associated protein). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It binds Cbl and plays a major role in regulating the insulin signaling pathway by enhancing insulin-induced phosphorylation of Cbl. Sorbs1, like vinexin, localizes at cell-ECM and cell-cell adhesion sites where it binds vinculin, paxillin, and afadin. It may function in the control of cell motility. Other interaction partners of Sorbs1 include c-Abl, Sos, flotillin, Grb4, ataxin-7, filamin C, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212849 [Multi-domain] Cd Length: 59 Bit Score: 40.75 E-value: 2.24e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVT--GLFPTNYVKM 1127
Cdd:cd11916     6 ALYSYAPQNDDELELRDGDIVDVMEKCDDGWFVGTSRRTKqfGTFPGNYVKL 57

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212808 [Multi-domain] Cd Length: 55 Bit Score: 40.41 E-value: 2.24e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQ---ENWWYGELKEKRGWFP 899
Cdd:cd11875     1 KARVLFDYEAENEDELTLREGDIVTILSKDcedKGWWKGELNGKRGVFP 49

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; N-terminal SH3 domain of the uncharacterized protein SH3 domain-containing protein 21, and similar uncharacterized domains, it belongs to the CD2AP-like_3 subfamily of proteins. The CD2AP-like_3 subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213018 [Multi-domain] Cd Length: 55 Bit Score: 40.53 E-value: 2.26e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd12142     2 CRVLFDYNPVAPDELALKKGDVIEVISKETEDEGWWEGELNGRRGFFPDNFVM 54

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and scaffold proteins and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212764 [Multi-domain] Cd Length: 54 Bit Score: 40.69 E-value: 2.28e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVdESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11830     1 TAKARYDFCARDMRELSLKEGDVVKI-YNKKGQQGWWRGEINGRIGWFPSTYVE 53

Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

Pssm-ID: 440809 [Multi-domain] Cd Length: 983 Bit Score: 46.08 E-value: 2.29e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  469 QRLKDRKRSLEIELEAvgNKHKQISSQLRDAKSKRQGQWAELELINQRRDVCITDINSLQLQFDEMQRQLNQLGPEKQRL 548
Cdd:COG1196   216 RELKEELKELEAELLL--LKLRELEAELEELEAELEELEAELEELEAELAELEAELEELRLELEELELELEEAQAEEYEL 293

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  549 ADRLvhftqnissplindvkqsvcekdrscRKLKEQLDVLERETTAKLSQMEQYNKEIKELRQKQSQQQDVLEQLRRVRS 628
Cdd:COG1196   294 LAEL--------------------------ARLEQDIARLEERRRELEERLEELEEELAELEEELEELEEELEELEEELE 347

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 688602146  629 DKLKELqrhrkeeeerkrkkeeeaarqAQLEQERLeqeeAERQRKLAQEREAKLREEQQRQALARLLEAQEQ 700
Cdd:COG1196   348 EAEEEL---------------------EEAEAELA----EAEEALLEAEAELAEAEEELEELAEELLEALRA 394

Second Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis. Together with other proteins, it induces membrane scission in yeast. Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This model represents the second C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212712 [Multi-domain] Cd Length: 51 Bit Score: 40.56 E-value: 2.29e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVdestVRE---TGWLYGSYSGNRGWFPESY 802
Cdd:cd11778     1 YVEALYDYEAQGDDEISIRVGDRIAV----IRGddgSGWTYGEINGVKGLFPTSY 51

First Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212707 [Multi-domain] Cd Length: 57 Bit Score: 40.49 E-value: 2.36e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEK-EGEWW----RGCIGD---QTGLFPSNY 981
Cdd:cd11773     2 YKALYDYEPQTEDELTIQEDDILYLLEKsDDDWWkvklKVNSSDddePVGLVPATY 57

N-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The N-terminal SH3 domain of the related protein GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212881 [Multi-domain] Cd Length: 54 Bit Score: 40.57 E-value: 2.36e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEKEGE--WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11948     1 EAVALYSFQATESDELPFQKGDILKILNMEDDqnWYKAELQGREGYIPKNYIK 53

Src Homology 3 domain of alpha-Pak Interactive eXchange factor; Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6) or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212993 Cd Length: 58 Bit Score: 40.76 E-value: 2.49e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVdeSTVRETGWLYGSYSGNRGWFPESY 802
Cdd:cd12060     5 KARFNFKQTNEDELSVCKGDIIYV--TRVEEGGWWEGTLNGKTGWFPSNY 52

Src Homology 3 domain of Nephrocystin (or Nephrocystin-1); Nephrocystin contains an SH3 domain involved in signaling pathways that regulate cell adhesion and cytoskeletal organization. It is a protein that in humans is associated with juvenile nephronophthisis, an inherited kidney disease characterized by renal fibrosis that lead to chronic renal failure in children. It is localized in cell-cell junctions in renal duct cells, and is known to interact with Ack1, an activated Cdc42-associated kinase. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212704 [Multi-domain] Cd Length: 54 Bit Score: 40.37 E-value: 2.63e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEK-EGEWW--RGCIGDQtGLFPSNYVKP 984
Cdd:cd11770     1 LYEALSDFQAEQEGDLSFKKGEVLRIISKrADGWWlaENSKGNR-GLVPKTYLKV 54

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 1; Shank1, also called SSTRIP (Somatostatin receptor-interacting protein), is a brain-specific protein that plays a role in the construction of postsynaptic density (PSD) and the maturation of dendritic spines. Mice deficient in Shank1 show altered PSD composition, thinner PSDs, smaller dendritic spines, and weaker basal synaptic transmission, although synaptic plasticity is normal. They show increased anxiety and impaired fear memory, but also show better spatial learning. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212915 [Multi-domain] Cd Length: 52 Bit Score: 40.38 E-value: 2.66e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11982     4 MAVKPYQSQAEGEISLSKGEKIKVLSVGEGGFWEGQVKGRVGWFPSDCV 52

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing proteins; ASAPs are Arf GTPase activating proteins (GAPs) and they function in regulating cell growth, migration, and invasion. They contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. Vertebrates contain at least three members, ASAP1, ASAP2, and ASAP3, but some ASAP3 proteins do not seem to harbor a C-terminal SH3 domain. ASAP1 and ASAP2 show GTPase activating protein (GAP) activity towards Arf1 and Arf5. They do not show GAP activity towards Arf6, but are able to mediate Arf6 signaling by binding stably to GTP-Arf6. ASAP3 is an Arf6-specific GAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212755 [Multi-domain] Cd Length: 53 Bit Score: 40.38 E-value: 2.74e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEG-EWWRGCI---GDQTGLFPSNY 981
Cdd:cd11821     4 ALYDCQADNDDELTFSEGEIIVVTGEEDdEWWEGHIegdPSRRGVFPVSF 53

Src homology 3 domain of Endophilin-A; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain three endophilin-A isoforms (A1, A2, and A3). Endophilin-A proteins are enriched in the brain and play multiple roles in receptor-mediated endocytosis. They tubulate membranes and regulate calcium influx into neurons to trigger the activation of the endocytic machinery. They are also involved in the sorting of plasma membrane proteins, actin filament assembly, and the uncoating of clathrin-coated vesicles for fusion with endosomes. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212737 [Multi-domain] Cd Length: 55 Bit Score: 40.32 E-value: 2.74e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  752 YRALYPFTARNSDELTL-EADCFI---QVDEStvretgWLYGSYSGNRGWFPESYAE 804
Cdd:cd11803     3 CRALYDFEPENEGELGFkEGDIITltnQIDEN------WYEGMVNGQSGFFPVNYVE 53

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and scaffold proteins and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212764 [Multi-domain] Cd Length: 54 Bit Score: 40.31 E-value: 2.81e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGE--WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11830     3 KARYDFCARDMRELSLKEGDVVKIYNKKGQqgWWRGEINGRIGWFPSTYVE 53

Src Homology 3 domain of Sorting nexin 18; SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. It binds FIP5 and is required for apical lumen formation. It may also play a role in axonal elongation. SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX18 also contains BAR and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212830 [Multi-domain] Cd Length: 55 Bit Score: 40.36 E-value: 2.91e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  753 RALYPFTARNSDELTL-EADCFIQVDESTVRetGWLYGSYS-GNRGWFPESYAE 804
Cdd:cd11897     3 RALYDFRSENPGEISLrEHEVLSLCSEQDIE--GWLEGVNSrGDRGLFPASYVE 54

Uncharacterized protein, contains DUF3084 domain [Function unknown];

Pssm-ID: 443500 [Multi-domain] Cd Length: 370 Bit Score: 45.28 E-value: 2.92e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  456 ELQTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRQGQWAELELINQRRDVCITDINSLQLQFDEMQ 535
Cdd:COG4372    63 QLEEELEQARSELEQLEEELEELNEQLQAAQAELAQAQEELESLQEEAEELQEELEELQKERQDLEQQRKQLEAQIAELQ 142

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  536 RQLNQLGPEKQRLADRLVHFTQNISSPLINDVKQSVCEKDRSCRKLKEQLDVLERETTAKLSQMEQYNKEIKELRQKQSQ 615
Cdd:COG4372   143 SEIAEREEELKELEEQLESLQEELAALEQELQALSEAEAEQALDELLKEANRNAEKEEELAEAEKLIESLPRELAEELLE 222

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  616 QQDVLEQLRRVRSDKLKELQRHRKEEEERKRKKEEEAARQAQLEQERLEQEEAERqRKLAQEREAKLREEQQRQALARLL 695
Cdd:COG4372   223 AKDSLEAKLGLALSALLDALELEEDKEELLEEVILKEIEELELAILVEKDTEEEE-LEIAALELEALEEAALELKLLALL 301

                         250       260       270
                  ....*....|....*....|....*....|....*..
gi 688602146  696 EAQEQARAKEEKRRAEEKERNELDVHTQSSLPFNSTE 732
Cdd:COG4372   302 LNLAALSLIGALEDALLAALLELAKKLELALAILLAE 338

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. Also included in this subfamily is the second C-terminal SH3 domain of Rho guanine nucleotide exchange factor 37 (ARHGEF37), whose function is still unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212734 [Multi-domain] Cd Length: 57 Bit Score: 40.43 E-value: 2.98e-04

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEK---EG--EWW----RGcigdQTGLFPSNYVKP 984
Cdd:cd11800     2 YYALYTFEARSPGELSVTEGQVVTVLEKhdlKGnpEWWlvedRG----KQGYVPSNYLAK 57

C-terminal Src Homology 3 domain of NADPH oxidase activator 1; Noxa1 is a homolog of p67phox and is a cytosolic subunit of the nonphagocytic NADPH oxidase complex Nox1, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Noxa1 is co-expressed with Nox1 in colon, stomach, uterus, prostate, and vascular smooth muscle cells, consistent with its regulatory role. It does not interact with p40phox, unlike p67phox, making Nox1 activity independent of p40phox, unlike Nox2. Noxa1 contains TPR, PB1, and C-terminal SH3 domains, but lacks the central SH3 domain that is present in p67phox. The TPR domain binds activated GTP-bound Rac. The C-terminal SH3 domain binds the polyproline motif found at the C-terminus of Noxo1, a homolog of p47phox. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212980 Cd Length: 53 Bit Score: 40.19 E-value: 3.00e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  935 VALYTYESPESGDLTFSAEDVV-LVTEKEGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd12047     3 VAQHDYSAQGPEDLEFSQGDTIdILSEVNQEWLEGHCDGRIGIFPKCFAVR 53

Second Src Homology 3 domain of SH3 domain containing ring finger protein 1, an E3 ubiquitin-protein ligase; SH3RF1 is also called POSH (Plenty of SH3s) or SH3MD2 (SH3 multiple domains protein 2). It is a scaffold protein that acts as an E3 ubiquitin-protein ligase. It plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. It contains an N-terminal RING finger domain and four SH3 domains. This model represents the second SH3 domain, located C-terminal of the first SH3 domain at the N-terminal half, of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212863 Cd Length: 55 Bit Score: 40.36 E-value: 3.06e-04

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                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1075 QVIAMYDY----KAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11930     1 QCKALYDFevkdKEADKDCLPFAKDDILTVIRRVDENWAEGMLGDKIGIFPISYV 55

Second Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212696 [Multi-domain] Cd Length: 57 Bit Score: 40.07 E-value: 3.10e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLEKQEN-----WWYGELKEKRGWFP 899
Cdd:cd11762     4 ALYDYEAQSDEELSFPEGAIIRILRKDDNgvddgWWEGEFNGRVGVFP 51

Src homology 3 domain of Type I fungal Myosins; Type I myosins (myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Saccharomyces cerevisiae has two myosins-I, Myo3 and Myo5, which are involved in endocytosis and the polarization of the actin cytoskeleton. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212792 [Multi-domain] Cd Length: 55 Bit Score: 40.06 E-value: 3.12e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVT--GLFPTNYVK 1126
Cdd:cd11858     4 ALYDFAGSVANELSLKKDDIVYIVQKEDNGWWLAKKLDESkeGWVPAAYLE 54

Src Homology 3 domain of Rho GTPase-activating protein 9 and similar proteins; This subfamily is composed of Rho GTPase-activating proteins including mammalian ARHGAP9, and vertebrate ARHGAPs 12 and 27. RhoGAPs (or ARHGAPs) bind to Rho proteins and enhance the hydrolysis rates of bound GTP. ARHGAP9 functions as a GAP for Rac and Cdc42, but not for RhoA. It negatively regulates cell migration and adhesion. It also acts as a docking protein for the MAP kinases Erk2 and p38alpha, and may facilitate cross-talk between the Rho GTPase and MAPK pathways to control actin remodeling. ARHGAP27, also called CAMGAP1, shows GAP activity towards Rac1 and Cdc42. It binds the adaptor protein CIN85 and may play a role in clathrin-mediated endocytosis. ARHGAP12 has been shown to display GAP activity towards Rac1. It plays a role in regulating HFG-driven cell growth and invasiveness. ARHGAPs in this subfamily contain SH3, WW, Pleckstin homology (PH), and RhoGAP domains. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212821 [Multi-domain] Cd Length: 54 Bit Score: 40.04 E-value: 3.14e-04

                          10        20        30
                  ....*....|....*....|....*....|....*..
gi 688602146 1075 QVIAMYD--YKAANKDEMSFQKGQLITVLNKDNPDWW 1109
Cdd:cd11888     1 YVVVLYPfeYTGKDGRKVSIKEGERFLLLKKSNDDWW 37

Second Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212834 [Multi-domain] Cd Length: 55 Bit Score: 40.02 E-value: 3.15e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146  756 YPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNRGWFPESY 802
Cdd:cd11901     8 FNYTAEREDELSLVKGTKVIVMEKC--SDGWWRGSYNGQVGWFPSNY 52

Third Src Homology 3 domain (SH3C) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CIN85. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212990 [Multi-domain] Cd Length: 56 Bit Score: 40.27 E-value: 3.16e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd12057     3 KVLFPYEAQNEDELTIKEGDIVTLISKDCIDAGWWEGELNGRRGVFPDNFVK 54

Src homology 3 domain of an unknown subfamily of proteins with similarity to Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212932 [Multi-domain] Cd Length: 56 Bit Score: 40.31 E-value: 3.16e-04

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                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE--WWRGCI-GDQTGLFPSNYV 982
Cdd:cd11999     6 AVYDYTGQEPDELSFKAGEELLKVEDEDEqgWCKGVTdGGAVGLYPANYV 55

First Src Homology 3 domain (SH3A) of CD2-associated protein and similar proteins; This subfamily is composed of the first SH3 domain (SH3A) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3A of both proteins bind to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic domain of the cell adhesion protein CD2. CIN85 SH3A binds to internal proline-rich motifs within the proline-rich region; this intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. CIN85 SH3A has also been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212806 [Multi-domain] Cd Length: 53 Bit Score: 39.94 E-value: 3.19e-04

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                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQvdESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11873     1 EVIVEFDYDAEEPDELTLKVGDIIT--NVKKMEEGWWEGTLNGKRGMFPDNFVK 52

Src Homology 3 domain of beta-Pak Interactive eXchange factor; Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212994 [Multi-domain] Cd Length: 54 Bit Score: 40.05 E-value: 3.21e-04

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                  ....*....|....*....|....*....|....*....|..
gi 688602146  866 DSHLGFCKDDIITVLEKQEN-WWYGELKEKRGWFPCSHVSVV 906
Cdd:cd12061    13 EDELSFSKGDVIHVTRVEEGgWWEGTHNGRTGWFPSNYVREI 54

Src homology 3 domain of Hematopoietic lineage cell-specific protein 1; HS1, also called HCLS1 (hematopoietic cell-specific Lyn substrate 1), is a cortactin homolog expressed specifically in hematopoietic cells. It is an actin regulatory protein that binds the Arp2/3 complex and stabilizes branched actin filaments. It is required for cell spreading and signaling in lymphocytes. It regulates cytoskeletal remodeling that controls lymphocyte trafficking, and it also affects tissue invasion and infiltration of leukemic B cells. Like cortactin, HS1 contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region binds the Arp2/3 complex and F-actin, while the C-terminal region acts as an adaptor or scaffold that can connect varied proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213006 [Multi-domain] Cd Length: 55 Bit Score: 40.20 E-value: 3.56e-04

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                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHV 903
Cdd:cd12073     3 AVALYDYQGEGDDEISFDPQETITDIEMvDEGWWKGTCHGHRGLFPANYV 52

C2 domain found in the Human chromosome 21 open reading frame 25 (C21orf25) protein; The members in this cd are named after the Human C21orf25 which contains a single C2 domain. Several other members contain a C1 domain downstream of the C2 domain. No other information on this protein is currently known. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 176060 [Multi-domain] Cd Length: 126 Bit Score: 41.97 E-value: 3.58e-04

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1513 LLVTVLEATELKpcKPNGKSNPYCELTMG--AQCYTSRHQPDTLNPKWSfncQFFIKDLYQD--VLCLTVFERDQFSPDD 1588
Cdd:cd08678     1 LLVKNIKANGLS--EAAGSSNPYCVLEMDepPQKYQSSTQKNTSNPFWD---EHFLFELSPNskELLFEVYDNGKKSDSK 75

                          90
                  ....*....|....
gi 688602146 1589 FLGRTEVPVATIKK 1602
Cdd:cd08678    76 FLGLAIVPFDELRK 89

EF-hand, calcium binding motif, found in homologs of mammalian apoptosis-linked gene 2 protein (ALG-2); The family includes some homologs of mammalian apoptosis-linked gene 2 protein (ALG-2) mainly found in lower eukaryotes, such as a parasitic protist Leishmarua major and a cellular slime mold Dictyostelium discoideum. These homologs contains five EF-hand motifs. Due to the presence of unfavorable residues at the Ca2+-coordinating positions, their non-canonical EF4 and EF5 hands may not bind Ca2+. Two Dictyostelium PEF proteins are the prototypes of this family. They may bind to cytoskeletal proteins and/or signal-transducing proteins localized to detergent-resistant membranes named lipid rafts, and occur as monomers or weak homo- or heterodimers like ALG-2. They can serve as a mediator for Ca2+ signaling-related Dictyostehum programmed cell death (PCD).

Pssm-ID: 320060 [Multi-domain] Cd Length: 163 Bit Score: 42.97 E-value: 3.65e-04

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 688602146  226 RQLFNSLDKLMSGYLSGPQVRNALTASNL-----TQTQLATIWflaDVDRDGQLRAEEFiLAMH 284
Cdd:cd16185     3 RQWFRAVDRDRSGSIDVNELQKALAGGGLlfslaTAEKLIRMF---DRDGNGTIDFEEF-AALH 62

Second Src Homology 3 domain (SH3B) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CIN85. SH3B has been shown to bind Cbl proline-rich peptides and ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212988 [Multi-domain] Cd Length: 53 Bit Score: 39.98 E-value: 3.70e-04

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                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVV-LVTEKEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd12055     4 VAFSYLPQNEDELELKVGDIIeVVGEVEEGWWEGVLNGKTGMFPSNFIK 52

Third Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the third SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212950 Cd Length: 53 Bit Score: 39.74 E-value: 3.73e-04

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                  ....*....|....*....|....*....|....*....|....*
gi 688602146 1081 DYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd12017     7 EFQATIQDGISFQKGQKVEVIDKNPSGWWYVKIDGKEGWAPSSYI 51

Second Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212834 [Multi-domain] Cd Length: 55 Bit Score: 40.02 E-value: 3.76e-04

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                  ....*....|....*....|....*....|....*....|....*.
gi 688602146  938 YTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYV 982
Cdd:cd11901     8 FNYTAEREDELSLVKGTKVIVMEKCSDgWWRGSYNGQVGWFPSNYV 53

C-terminal (or second) Src homology 3 domain of VAV2 protein; VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212910 [Multi-domain] Cd Length: 58 Bit Score: 40.00 E-value: 4.01e-04

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                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  750 TTYRALYPFTARNSDELTLEADCFIQVDESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11977     1 GTAVARYNFAARDMRELSLREGDVVRIYSRIGGDQGWWKGETNGRIGWFPSTYVE 55

Src homology 3 domain of JNK-interacting protein 1; JNK-interacting protein 1 (JIP1) is also called Islet-brain 1 (IB1) or Mitogen-activated protein kinase 8-interacting protein 1 (MAPK8IP1). It is highly expressed in neurons, where it functions as an adaptor linking motor to cargo during axonal transport. It also affects microtubule dynamics in neurons. JIP1 is also found in pancreatic beta-cells, where it is involved in regulating insulin secretion. In addition to a JNK binding domain, JIP1 also contains SH3 and Phosphotyrosine-binding (PTB) domains. Its SH3 domain homodimerizes at the interface usually involved in proline-rich ligand recognition, despite the lack of this motif in the domain itself. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212876 Cd Length: 55 Bit Score: 39.97 E-value: 4.12e-04

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                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDestVRETGWLYGSY---SGNRGWFPESYA 803
Cdd:cd11943     1 THRAVFRFVPRHPDELELEVDDPLLVE---VQAEDYWYEAYnmrTGARGIFPAYYA 53

Src homology 3 domain of the Rho guanine nucleotide exchange factors ARHGEF5 and ARHGEF19; ARHGEF5, also called ephexin-3 or TIM (Transforming immortalized mammary oncogene), is a potent activator of RhoA and it plays roles in regulating cell shape, adhesion, and migration. It binds to the SH3 domain of Src and is involved in regulating Src-induced podosome formation. ARHGEF19, also called ephexin-2 or WGEF (weak-similarity GEF), is highly expressed in the intestine, liver, heart and kidney. It activates RhoA, Cdc42, and Rac 1, and has been shown to activate RhoA in the Wnt-PCP (planar cell polarity) pathway. It is involved in the regulation of cell polarity and cytoskeletal reorganization. ARHGEF5 and ARHGEF19 contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and SH3 domains. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212873 Cd Length: 55 Bit Score: 39.78 E-value: 4.36e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  758 FTARNSDELTLEADCFIQVDESTvrETGWLYGSY--SGNRGWFPESYAE 804
Cdd:cd11940     8 YKAQENDELTLEKADIIMVRQQS--SDGWLEGVRlsDGERGWFPQSHVE 54

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

Pssm-ID: 274008 [Multi-domain] Cd Length: 1179 Bit Score: 45.05 E-value: 4.40e-04

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   455 VELQTQKEKEQNDIQRLKDRKRSLEIELEavgnkhkQISSQLRDAKSKRQGQWAELELINQRRDVCITDINSLQLQFDEM 534
Cdd:TIGR02168  841 EDLEEQIEELSEDIESLAAEIEELEELIE-------ELESELEALLNERASLEEALALLRSELEELSEELRELESKRSEL 913

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   535 QRQL-------NQLGPEKQRLADRLVHFTQNISSPLI---NDVKQSVCEKDRSCRKLKEQLDVLERETTA----KLSQME 600
Cdd:TIGR02168  914 RRELeelreklAQLELRLEGLEVRIDNLQERLSEEYSltlEEAEALENKIEDDEEEARRRLKRLENKIKElgpvNLAAIE 993

                          170       180       190
                   ....*....|....*....|....*....|
gi 688602146   601 QYnKEIKELRQKQSQQQDVL----EQLRRV 626
Cdd:TIGR02168  994 EY-EELKERYDFLTAQKEDLteakETLEEA 1022

C-terminal (or second) Src homology 3 domain of VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration. It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212911 [Multi-domain] Cd Length: 56 Bit Score: 39.62 E-value: 4.46e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGE--WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11978     4 IARYDFCARDMRELSLLKGDVVKIYTKMSTngWWRGEVNGRVGWFPSTYVE 54

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212882 [Multi-domain] Cd Length: 53 Bit Score: 39.82 E-value: 4.51e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKEKRGWFPCSHVS 904
Cdd:cd11949     4 ALFDFDPQEDGELGFRRGDFIEVMDNSDpNWWKGACHGQTGMFPRNYVT 52

Third (or C-terminal) Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212850 [Multi-domain] Cd Length: 61 Bit Score: 39.59 E-value: 5.24e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVT--GLFPTNYVK 1126
Cdd:cd11917     9 ALYNYMPRNEDELELREGDVIDVMEKCDDGWFVGTSRRTKffGTFPGNYVK 59

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member, Neural precursor cell Expressed, Developmentally Down-regulated 9; NEDD9 is also called human enhancer of filamentation 1 (HEF1) or CAS-L (Crk-associated substrate in lymphocyte). It was first described as a gene predominantly expressed in early embryonic brain, and was also isolated from a screen of human proteins that regulate filamentous budding in yeast, and as a tyrosine phosphorylated protein in lymphocytes. It promotes metastasis in different solid tumors. NEDD9 localizes in focal adhesions and associates with FAK and Abl kinase. It also interacts with SMAD3 and the proteasomal machinery which allows its rapid turnover; these interactions are not shared by other CAS proteins. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212935 Cd Length: 57 Bit Score: 39.58 E-value: 5.45e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDN---PDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd12002     4 ALYDNVPECAEELAFRKGDILTVIEQNTgglEGWWLCSLHGRQGIAPGNRLKL 56

N-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also have roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The N-terminal SH3 domain of the related protein GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212880 [Multi-domain] Cd Length: 52 Bit Score: 39.39 E-value: 5.52e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11947     1 EARGKFDFTASGEDELSFKKGDVLKILSSDDIWFKAELNGEEGYVPKNFVDI 52

C-terminal (or second) Src homology 3 domain of VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration. It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212911 [Multi-domain] Cd Length: 56 Bit Score: 39.62 E-value: 5.76e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  754 ALYPFTARNSDELTLEADCFIQVdESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11978     5 ARYDFCARDMRELSLLKGDVVKI-YTKMSTNGWWRGEVNGRVGWFPSTYVE 54

Second Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212696 [Multi-domain] Cd Length: 57 Bit Score: 39.30 E-value: 5.77e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE-----WWRGCIGDQTGLFPS 979
Cdd:cd11762     4 ALYDYEAQSDEELSFPEGAIIRILRKDDNgvddgWWEGEFNGRVGVFPS 52

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the peroxisomal membrane, contains two transmembrane regions and a C-terminal SH3 domain. It binds to the peroxisomal targeting type I (PTS1) receptor Pex5p and the docking factor Pex14p through its SH3 domain. It is essential for both PTS1 and PTS2 protein import pathways into the peroxisomal matrix. Pex13p binds Pex14p, which contains a PxxP motif, in a classical fashion to the proline-rich ligand binding site of its SH3 domain. It binds the WxxxF/Y motif of Pex5p in a novel site that does not compete with Pex14p binding. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212705 [Multi-domain] Cd Length: 60 Bit Score: 39.57 E-value: 5.85e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  936 ALYTY--ESPEsGDLTFSAEDVVLVTEK------EGEWWRGCIGD-QTGLFPSNYV 982
Cdd:cd11771     4 ALYDFtpENPE-MELSLKKGDIVAVLSKtdplgrDSEWWKGRTRDgRIGWFPSNYV 58

Third Src homology 3 domain of Rab3-interacting molecules (RIMs) binding proteins; RIMs binding proteins (RBPs, RIM-BPs) associate with calcium channels present in photoreceptors, neurons, and hair cells; they interact simultaneously with specific calcium channel subunits, and active zone proteins, RIM1 and RIM2. RIMs are part of the matrix at the presynaptic active zone and are associated with synaptic vesicles through their interaction with the small GTPase Rab3. RIM-BPs play a role in regulating synaptic transmission by serving as adaptors and linking calcium channels with the synaptic vesicle release machinery. RIM-BPs contain three SH3 domains and two to three fibronectin III repeats. Invertebrates contain one, while vertebrates contain at least two RIM-BPs, RIM-BP1 and RIM-BP2. RIM-BP1 is also called peripheral-type benzodiazapine receptor associated protein 1 (PRAX-1). Mammals contain a third protein, RIM-BP3. RIM-BP1 and RIM-BP2 are predominantly expressed in the brain where they display overlapping but distinct expression patterns, while RIM-BP3 is almost exclusively expressed in the testis and is essential in spermiogenesis. The SH3 domains of RIM-BPs bind to the PxxP motifs of RIM1, RIM2, and L-type (alpha1D) and N-type (alpha1B) calcium channel subunits. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212946 Cd Length: 61 Bit Score: 39.67 E-value: 5.93e-04

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1075 QVIAMYDYK----AANKD---EMSFQKGQLITVLNK-DNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12013     1 RMVALFDYDpresSPNVDaevELSFRAGDIITVFGEmDEDGFYYGELNGQRGLVPSNFLE 60

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing proteins; ASAPs are Arf GTPase activating proteins (GAPs) and they function in regulating cell growth, migration, and invasion. They contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. Vertebrates contain at least three members, ASAP1, ASAP2, and ASAP3, but some ASAP3 proteins do not seem to harbor a C-terminal SH3 domain. ASAP1 and ASAP2 show GTPase activating protein (GAP) activity towards Arf1 and Arf5. They do not show GAP activity towards Arf6, but are able to mediate Arf6 signaling by binding stably to GTP-Arf6. ASAP3 is an Arf6-specific GAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212755 [Multi-domain] Cd Length: 53 Bit Score: 39.22 E-value: 5.96e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  854 QAVALCEwsAKTDSHLGFCKDDIITVL-EKQENWWYGELK---EKRGWFPCS 901
Cdd:cd11821     3 RALYDCQ--ADNDDELTFSEGEIIVVTgEEDDEWWEGHIEgdpSRRGVFPVS 52

Src Homology 3 domain of Cytokinesis protein 3 and similar proteins; Cytokinesis protein 3 (Cyk3 or Cyk3p) is a component of the actomyosin ring independent cytokinesis pathway in yeast. It interacts with Inn1 and facilitates its recruitment to the bud neck, thereby promoting cytokinesis. Cyk3p contains an N-terminal SH3 domain and a C-terminal transglutaminase-like domain. The Cyk3p SH3 domain binds to the C-terminal proline-rich region of Inn1. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212822 Cd Length: 53 Bit Score: 39.40 E-value: 5.97e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTE-KEGEWWRG-CIGDQT-GLFPSNYV 982
Cdd:cd11889     4 AVYSWAGETEGDLGFLEGDLIEVLSiGDGSWWSGkLRRNGAeGIFPSNFV 53

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If (MyoIf) are nonmuscle, unconventional, long tailed, class I myosins containing an N-terminal motor domain and a myosin tail with TH1, TH2, and SH3 domains. MyoIe interacts with the endocytic proteins, dynamin and synaptojanin-1, through its SH3 domain; it may play a role in clathrin-dependent endocytosis. In the kidney, MyoIe is critical for podocyte function and normal glomerular filtration. Mutations in MyoIe is associated with focal segmental glomerulosclerosis, a disease characterized by massive proteinuria and progression to end-stage kidney disease. MyoIf is predominantly expressed in the immune system; it plays a role in immune cell motility and innate immunity. Mutations in MyoIf may be associated with the loss of hearing. The MyoIf gene has also been found to be fused to the MLL (Mixed lineage leukemia) gene in infant acute myeloid leukemias (AML). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212761 [Multi-domain] Cd Length: 53 Bit Score: 39.32 E-value: 6.02e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVL-EKQENWWYGELKEKRGWFPCSHV 903
Cdd:cd11827     1 QCKALYAYDAQDTDELSFNEGDIIEILkEDPSGWWTGRLRGKEGLFPGNYV 51

Second Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212835 [Multi-domain] Cd Length: 55 Bit Score: 39.22 E-value: 6.10e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146  756 YPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNRGWFPESY 802
Cdd:cd11902     7 FAYVAEREDELSLVKGSRVTVMEKC--SDGWWRGSYNGQIGWFPSNY 51

First Src Homology 3 domain (SH3A) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CIN85; SH3A binds to internal proline-rich motifs within the proline-rich region. This intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. SH3A has also been shown to bind ubiquitin and to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic end of the cell adhesion protein CD2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212985 [Multi-domain] Cd Length: 53 Bit Score: 39.11 E-value: 6.25e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEKQEN-WWYGELKEKRGWFP 899
Cdd:cd12052     1 EAIVEFDYKAQHEDELTITVGDIITKIKKDDGgWWEGEIKGRRGLFP 47

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 39.54 E-value: 6.33e-04

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 688602146   224 KYRQLFNSLDKLMSGYLSGPQVRNALT----ASNLTQTQLATIWFLADVDRDGQLRAEEFILAM 283
Cdd:pfam13499    3 KLKEAFKLLDSDGDGYLDVEELKKLLRkleeGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

Src homology 3 domain of SH3 and multiple ankyrin repeat domains (Shank) proteins; Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. They bind a variety of membrane and cytosolic proteins, and exist in alternatively spliced isoforms. They are highly enriched in postsynaptic density (PSD) where they interact with the cytoskeleton and with postsynaptic membrane receptors including NMDA and glutamate receptors. They are crucial in the construction and organization of the PSD and dendritic spines of excitatory synapses. There are three members of this family (Shank1, Shank2, Shank3) which show distinct and cell-type specific patterns of expression. Shank1 is brain-specific; Shank2 is found in neurons, glia, endocrine cells, liver, and kidney; Shank3 is widely expressed. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212766 Cd Length: 50 Bit Score: 38.96 E-value: 6.43e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFP 1121
Cdd:cd11832     1 YFIAVKSYSPQEEGEISLHKGDRVKVLSIGEGGFWEGSVRGRTGWFP 47

First Src Homology 3 domain of SH3 domain containing ring finger protein 1, an E3 ubiquitin-protein ligase; SH3RF1 is also called POSH (Plenty of SH3s) or SH3MD2 (SH3 multiple domains protein 2). It is a scaffold protein that acts as an E3 ubiquitin-protein ligase. It plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. It contains an N-terminal RING finger domain and four SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212860 Cd Length: 54 Bit Score: 39.16 E-value: 6.61e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIItVLEKQ--ENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11927     3 AKALYNYEGKEPGDLKFSKGDII-ILRRQvdENWYHGEVNGIHGFFPTNFVQI 54

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

Pssm-ID: 443941 [Multi-domain] Cd Length: 1089 Bit Score: 44.52 E-value: 6.66e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  468 IQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRQgqwaelELINQRRDVCITDINSLQLQFDEMQRQLNqlgpEKQR 547
Cdd:COG4913   290 LELLEAELEELRAELARLEAELERLEARLDALREELD------ELEAQIRGNGGDRLEQLEREIERLERELE----ERER 359

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  548 LADRLVHFTQNISSPLINDvKQSVCEKDRSCRKLKEQLDVLERETTAKLSQMEQynkEIKELRQKQSQQQDVLEQLRRVR 627
Cdd:COG4913   360 RRARLEALLAALGLPLPAS-AEEFAALRAEAAALLEALEEELEALEEALAEAEA---ALRDLRRELRELEAEIASLERRK 435


                  .
gi 688602146  628 S 628
Cdd:COG4913   436 S 436

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase 2; GRAF2, also called Rho GTPase activating protein 10 (ARHGAP10) or PS-GAP, is a GAP with activity towards Cdc42 and RhoA. It regulates caspase-activated p21-activated protein kinase-2 (PAK-2p34). GRAF2 interacts with PAK-2p34, leading to its stabilization and decrease of cell death. It is highly expressed in skeletal muscle, and is involved in alpha-catenin recruitment at cell-cell junctions. GRAF2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212998 [Multi-domain] Cd Length: 54 Bit Score: 39.20 E-value: 6.70e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLI-TVLNKDNPDWWKGEVAGVTGLFPTNYVKM 1127
Cdd:cd12065     4 AVYPCEAEHSSELSFEVGAIFeDVTLSREPGWLEGTLNGKRGLIPENYVEI 54

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase; GRAF, also called Rho GTPase activating protein 26 (ARHGAP26), Oligophrenin-1-like (OPHN1L) or GRAF1, is a GAP with activity towards RhoA and Cdc42 and is only weakly active towards Rac1. It influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase (FAK), which is a critical component of integrin signaling. It is essential for the major clathrin-independent endocytic pathway mediated by pleiomorphic membranes. GRAF contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212997 Cd Length: 56 Bit Score: 39.33 E-value: 6.79e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLI-TVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12064     5 ALYACKAEHDSELSFTAGTVFdNVHPSQEPGWLEGTLNGKTGLIPENYVE 54

Src Homology 3 domain of Myosin XVb; Myosin XVb, also called KIAA1783, was named based on its similarity with myosin XVa. It is a transcribed and unprocessed pseudogene whose predicted amino acid sequence contains mutated or deleted amino acid residues that are normally conserved and important for myosin function. The related myosin XVa is important for normal growth of mechanosensory stereocilia of inner ear hair cells. Myosin XVa contains a unique N-terminal extension followed by a motor domain, light chain-binding IQ motifs, and a tail consisting of a pair of MyTH4-FERM tandems separated by a SH3 domain, and a PDZ domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 213001 Cd Length: 55 Bit Score: 39.09 E-value: 7.01e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKD--NPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12068     2 VVALRSYITDDKSLLSFHRGDLIKLLPMAglEPGWQFGSTGGRSGLFPADIVQ 54

Src Homology 3 domain of Membrane Protein, Palmitoylated 1 (or MAGUK p55 subfamily member 1)-like proteins; This subfamily includes MPP1, CASK (Calcium/calmodulin-dependent Serine protein Kinase), Caenorhabditis elegans lin-2, and similar proteins. MPP1 and CASK are scaffolding proteins from the MAGUK (membrane-associated guanylate kinase) protein family, which is characterized by the presence of a core of three domains: PDZ, SH3, and guanylate kinase (GuK). In addition, they also have the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. CASK and lin-2 also contain an N-terminal calmodulin-dependent kinase (CaMK)-like domain and two L27 domains. MPP1 is ubiquitously-expressed and plays roles in regulating neutrophil polarity, cell shape, hair cell development, and neural development and patterning of the retina. CASK is highly expressed in the mammalian nervous system and plays roles in synaptic protein targeting, neural development, and gene expression regulation. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212968 Cd Length: 62 Bit Score: 39.34 E-value: 7.57e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 688602146 1076 VIAMYDYKAANKD-------EMSFQKGQLITVLNKDNPDWWKGEVAG----VTGLFPT 1122
Cdd:cd12035     2 VRAQFDYDPSKDDlipcqqaGIAFKTGDILQIISKDDHNWWQARKPGaskePAGLIPS 59

Src homology 3 domain of SH3 domain containing Ysc84-like 1 (SH3YL1) protein; SH3YL1 localizes to the plasma membrane and is required for dorsal ruffle formation. It binds phosphoinositides (PIs) with high affinity through its N-terminal SYLF domain (also called DUF500). In addition, SH3YL1 contains a C-terminal SH3 domain which has been reported to bind to N-WASP, dynamin 2, and SHIP2 (a PI 5-phosphatase). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212775 Cd Length: 54 Bit Score: 38.91 E-value: 7.71e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK---QENWWYGELKEKRGWFPCSHVS 904
Cdd:cd11841     1 EVTALYSFEGQQPCDLSFQAGDRITVLTRtdsQFDWWEGRLRGRVGIFPANYVS 54

C-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domains (SH3c) of the related proteins, GRB2 and GRAP2, have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212884 Cd Length: 53 Bit Score: 39.01 E-value: 7.97e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 688602146  860 EWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKEKRGWFPCSHV 903
Cdd:cd11951     7 DFSAEDPSQLSFRRGDIIEVLDCPDpNWWRGRISGRVGFFPRNYV 51

Src Homology 3 domain of Cytokinesis protein 3 and similar proteins; Cytokinesis protein 3 (Cyk3 or Cyk3p) is a component of the actomyosin ring independent cytokinesis pathway in yeast. It interacts with Inn1 and facilitates its recruitment to the bud neck, thereby promoting cytokinesis. Cyk3p contains an N-terminal SH3 domain and a C-terminal transglutaminase-like domain. The Cyk3p SH3 domain binds to the C-terminal proline-rich region of Inn1. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212822 Cd Length: 53 Bit Score: 39.02 E-value: 8.59e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLE-KQENWWYGELKEKR--GWFPCSHV 903
Cdd:cd11889     4 AVYSWAGETEGDLGFLEGDLIEVLSiGDGSWWSGKLRRNGaeGIFPSNFV 53

C-terminal (or second) Src homology 3 domain of VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration. It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212911 [Multi-domain] Cd Length: 56 Bit Score: 38.85 E-value: 8.63e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLEKQ--ENWWYGELKEKRGWFPCSHV 903
Cdd:cd11978     3 AIARYDFCARDMRELSLLKGDVVKIYTKMstNGWWRGEVNGRVGWFPSTYV 53

First Src Homology 3 domain of SH3 domain containing ring finger 2; SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal RING finger domain and three SH3 domains. This model represents the first SH3 domain, located at the N-terminal half, of SH3RF2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212862 Cd Length: 54 Bit Score: 38.77 E-value: 8.77e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11929     5 ALCNYRGHNPGDLKFNKGDVILLRRQLDEnWYLGEINGVSGIFPASSVE 53

Src homology 3 domain of Signal Transducing Adaptor Molecule 2; STAM2, also called EAST (Epidermal growth factor receptor-associated protein with SH3 and TAM domain) or Hbp (Hrs binding protein), is part of the endosomal sorting complex required for transport (ESCRT-0). It plays a role in sorting mono-ubiquinated endosomal cargo for trafficking to the lysosome for degradation. It is also involved in the regulation of exocytosis. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212896 [Multi-domain] Cd Length: 57 Bit Score: 38.85 E-value: 8.88e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKEKRGWFPCSHVS 904
Cdd:cd11963     6 ALYDFEAVEDNELTFKHGEIIIVLDDSDaNWWKGENHRGVGLFPSNFVT 54

Src homology 3 domain of the Rho guanine nucleotide exchange factors ARHGEF16 and ARHGEF26; ARHGEF16, also called ephexin-4, acts as a GEF for RhoG, activating it by exchanging bound GDP for free GTP. RhoG is a small GTPase that is a crucial regulator of Rac in migrating cells. ARHGEF16 interacts directly with the ephrin receptor EphA2 and mediates cell migration and invasion in breast cancer cells by activating RhoG. ARHGEF26, also called SGEF (SH3 domain-containing guanine exchange factor), also activates RhoG. It is highly expressed in liver and may play a role in regulating membrane dynamics. ARHGEF16 and ARHGEF26 contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and SH3 domains. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212871 Cd Length: 55 Bit Score: 39.06 E-value: 8.89e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  758 FTARNSDELTLE-ADCFIQVDEStvrETGWLYGSY--SGNRGWFPESYAE 804
Cdd:cd11938     8 YTAKQPDELSLQqADVVLVLQTE---SDGWYYGERlrDGERGWFPSSCAK 54

Src Homology 3 domain of SH3 domain-binding protein 4; SH3 domain-binding protein 4 (SH3BP4) is also called transferrin receptor trafficking protein (TTP). SH3BP4 is an endocytic accessory protein that interacts with endocytic proteins including clathrin and dynamin, and regulates the internalization of the transferrin receptor (TfR). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212691 Cd Length: 52 Bit Score: 38.85 E-value: 8.95e-04

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd11757     1 EVVAIKDYCPTNFTTLKFSKGDHLYVLDTSGGEWWYAHNTTEMGYIPSSYVQ 52

Second Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212835 [Multi-domain] Cd Length: 55 Bit Score: 38.83 E-value: 9.59e-04

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 688602146  938 YTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYV 982
Cdd:cd11902     7 FAYVAEREDELSLVKGSRVTVMEKCSDgWWRGSYNGQIGWFPSNYV 52

Third Src homology 3 domain (or SH3C) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (SH3C) of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212925 Cd Length: 52 Bit Score: 38.84 E-value: 1.02e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLEKQENWWYGELKEKRGWFPCSHV 903
Cdd:cd11992     3 IALYPYSSSEPGDLTFNEGEEILVTQKDGEWWTGSIEDRTGIFPSNYV 50

N-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The N-terminal SH3 domain of the related protein GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212881 [Multi-domain] Cd Length: 54 Bit Score: 38.64 E-value: 1.06e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVL--EKQENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11948     1 EAVALYSFQATESDELPFQKGDILKILnmEDDQNWYKAELQGREGYIPKNYIKV 54

Src homology 3 domain of the Rho guanine nucleotide exchange factor ARHGEF9; ARHGEF9, also called PEM2 or collybistin, selectively activates Cdc42 by exchanging bound GDP for free GTP. It is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. Mutations in the ARHGEF9 gene cause X-linked mental retardation with associated features like seizures, hyper-anxiety, aggressive behavior, and sensory hyperarousal. ARHGEF9 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212908 Cd Length: 62 Bit Score: 38.92 E-value: 1.08e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 688602146  866 DSHLGFCKDDIITVLE-KQENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd11975    18 NRELAFKAGDVIKVLDaSNKDWWWGQIDDEEGWFPASFVRL 58

Src homology 3 domain of Protein arginine N-methyltransferase 2; PRMT2, also called HRMT1L1, belongs to the arginine methyltransferase protein family. It functions as a coactivator to both estrogen receptor alpha (ER-alpha) and androgen receptor (AR), presumably through arginine methylation. The ER-alpha transcription factor is involved in cell proliferation, differentiation, morphogenesis, and apoptosis, and is also implicated in the development and progression of breast cancer. PRMT2 and its variants are upregulated in breast cancer cells and may be involved in modulating the ER-alpha signaling pathway during formation of breast cancer. PRMT2 also plays a role in regulating the function of E2F transcription factors, which are critical cell cycle regulators, by binding to the retinoblastoma gene product (RB). It contains an N-terminal SH3 domain and an AdoMet binding domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212740 [Multi-domain] Cd Length: 53 Bit Score: 38.53 E-value: 1.10e-03

                          10        20        30
                  ....*....|....*....|....*....|.
gi 688602146 1010 ATTPEQLSLTPGQLIVVLHKNSNSWWLGELQ 1040
Cdd:cd11806    10 ATDDSQLSFESGDKLLVLRKPSVDWWWAEHN 40

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The N-terminal SH3 domain of GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212738 [Multi-domain] Cd Length: 52 Bit Score: 38.49 E-value: 1.17e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  933 EYVALYTYESPESGDLTFSAEDV--VLVTEKEGEWWRGCIGDQTGLFPSNYV 982
Cdd:cd11804     1 EAVAKHDFKATAEDELSFKKGSIlkVLNMEDDPNWYKAELDGKEGLIPKNYI 52

C-terminal Src Homology 3 domain of Nebulin; Nebulin is a giant filamentous protein (600-900 kD) that is expressed abundantly in skeletal muscle. It binds to actin thin filaments and regulates its assembly and function. Nebulin was thought to be part of a molecular ruler complex that is critical in determining the lengths of actin thin filaments in skeletal muscle since its length, which varies due to alternative splicing, correlates with the length of thin filaments in various muscle types. Recent studies indicate that nebulin regulates thin filament length by stabilizing the filaments and preventing depolymerization. Mutations in nebulin can cause nemaline myopathy, characterized by muscle weakness which can be severe and can lead to neonatal lethality. Nebulin contains an N-terminal LIM domain, many nebulin repeats/super repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212866 [Multi-domain] Cd Length: 58 Bit Score: 38.84 E-value: 1.17e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  751 TYRALYPFTARNSDELTL-EADCFIQVdeSTVREtGWLYGSY--SGNRGWFPESYAE 804
Cdd:cd11933     3 SFRAMYDYRAADDDEVSFkDGDTIVNV--QTIDE-GWMYGTVqrTGKTGMLPANYVE 56

Second Src Homology 3 domain (SH3B) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CD2AP. SH3B binds to c-Cbl in a site (TPSSRPLR is the core binding motif) distinct from the c-Cbl/SH3A binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212987 [Multi-domain] Cd Length: 55 Bit Score: 38.41 E-value: 1.19e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd12054     4 KVLFEYVPQNEDELELKVGDIIDINEEV--EEGWWSGTLNGKSGLFPSNFVK 53

C-terminal Src Homology 3 domain of the Nebulin family of proteins; Nebulin family proteins contain multiple nebulin repeats, and may contain an N-terminal LIM domain and/or a C-terminal SH3 domain. They have molecular weights ranging from 34 to 900 kD, depending on the number of nebulin repeats, and they all bind actin. They are involved in the regulation of actin filament architecture and function as stabilizers and scaffolds for cytoskeletal structures with which they associate, such as long actin filaments or focal adhesions. Nebulin family proteins that contain a C-terminal SH3 domain include the giant filamentous protein nebulin, nebulette, Lasp1, and Lasp2. Lasp2, also called LIM-nebulette, is an alternatively spliced variant of nebulette. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212723 [Multi-domain] Cd Length: 55 Bit Score: 38.45 E-value: 1.21e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCI---GdQTGLFPSNYVKP 984
Cdd:cd11789     2 YRAMYDYAAADDDEVSFQEGDVIINVEIIDDgWMEGTVqrtG-QSGMLPANYVEL 55

Src homology 3 domain of Rho GTPase-activating proteins 32 and 33, and similar proteins; Members of this family contain N-terminal PX and Src Homology 3 (SH3) domains, a central Rho GAP domain, and C-terminal extensions. RhoGAPs (or ARHGAPs) bind to Rho proteins and enhance the hydrolysis rates of bound GTP. ARHGAP32 is also called RICS, PX-RICS, p250GAP, or p200RhoGAP. It is a Rho GTPase-activating protein for Cdc42 and Rac1, and is implicated in the regulation of postsynaptic signaling and neurite outgrowth. PX-RICS, a variant of RICS that contain PX and SH3 domains, is the main isoform expressed during neural development. It is involved in neural functions including axon and dendrite extension, postnatal remodeling, and fine-tuning of neural circuits during early brain development. ARHGAP33, also called sorting nexin 26 or TCGAP (Tc10/CDC42 GTPase-activating protein), is widely expressed in the brain where it is involved in regulating the outgrowth of axons and dendrites and is regulated by the protein tyrosine kinase Fyn. It is translocated to the plasma membrane in adipocytes in response to insulin and may be involved in the regulation of insulin-stimulated glucose transport. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212769 [Multi-domain] Cd Length: 54 Bit Score: 38.58 E-value: 1.21e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146  940 YESPESGDLTFSAEDVVLVTE----KEGEWWRGCIGDQTGLFPSNYV 982
Cdd:cd11835     8 YTAQAPDELSLEVGDIVSVIDmpppEESTWWRGKKGFQVGFFPSECV 54

C2 domain in Protein Kinase C (PKC) epsilon; A single C2 domain is found in PKC epsilon. The PKC family of serine/threonine kinases regulates apoptosis, proliferation, migration, motility, chemo-resistance, and differentiation. There are 3 groups: group 1 (alpha, betaI, beta II, gamma) which require phospholipids and calcium, group 2 (delta, epsilon, theta, eta) which do not require calcium for activation, and group 3 (xi, iota/lambda) which are atypical and can be activated in the absence of diacylglycerol and calcium. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have a type-II topology.

Pssm-ID: 175981 [Multi-domain] Cd Length: 132 Bit Score: 40.72 E-value: 1.26e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKPCK------PNGKS----NPYCEL----TMGAQCYTsrhQPDTLNPKWSfncQFFIKDLYQDV-LC 1575
Cdd:cd04014     4 GTLKIKICEAVDLKPTDwstrhaVPKKGsqllDPYVSIdvddTHIGKTST---KPKTNSPVWN---EEFTTEVHNGRnLE 77

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146 1576 LTVFERDQFSPDDFLGRTEVPVATIKKDQDGKGPLVRRLllhEvPTGEVKVRLDLQ 1631
Cdd:cd04014    78 LTVFHDAAIGPDDFVANCTISFEDLIQRGSGSFDLWVDL---E-PQGKLHVKIELK 129

First or N-terminal Src homology 3 domain of the p47phox subunit of NADPH oxidase, also called Neutrophil Cytosolic Factor 1; p47phox, or NCF1, is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p47phox is required for activation of NADH oxidase and plays a role in translocation. It contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), a polybasic/autoinhibitory region, and a C-terminal proline-rich region (PRR). This model characterizes the first SH3 domain (or N-SH3) of p47phox. In its inactive state, the tandem SH3 domains interact intramolecularly with the autoinhibitory region; upon activation, the tandem SH3 domains are exposed through a conformational change, resulting in their binding to the PRR of p22phox and the activation of NADPH oxidase. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212954 [Multi-domain] Cd Length: 53 Bit Score: 38.40 E-value: 1.27e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd12021     1 TYRAIADYEKSSKSEMALKTGDVVEVVEKS--ENGWWFCQLKAKRGWVPASYLE 52

Src homology 3 domain of ephexin-1-like SH3 domain containing Rho guanine nucleotide exchange factors; Members of this family contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and C-terminal SH3 domains. They include the Rho guanine nucleotide exchange factors ARHGEF5, ARHGEF16, ARHGEF19, ARHGEF26, ARHGEF27 (also called ephexin-1), and similar proteins, and are also called ephexins because they interact directly with ephrin A receptors. GEFs interact with Rho GTPases via their DH domains to catalyze nucleotide exchange by stabilizing the nucleotide-free GTPase intermediate. They play important roles in neuronal development. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212727 [Multi-domain] Cd Length: 55 Bit Score: 38.47 E-value: 1.27e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGE-LKE-KRGWFPCSHV 903
Cdd:cd11793     1 QVQCVHAYTAQQPDELTLEEGDVVNVLRKmPDGWYEGErLRDgERGWFPSSYT 53

Src homology 3 domain of Abl Interactor 1; Abi1, also called e3B1, is a central regulator of actin cytoskeletal reorganization through interactions with many protein complexes. It is part of WAVE, a nucleation-promoting factor complex, that links Rac 1 activation to actin polymerization causing lamellipodia protrusion at the plasma membrane. Abi1 interact with formins to promote protrusions at the leading edge of motile cells. It also is a target of alpha4 integrin, regulating membrane protrusions at sites of integrin engagement. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212904 [Multi-domain] Cd Length: 59 Bit Score: 38.46 E-value: 1.29e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  935 VALYTYESPESGDLTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNYVK 983
Cdd:cd11971     3 VAIYDYSKDKDDELSFMEGAIIYVIKKNDDgWYEGVCNGVTGLFPGNYVE 52

Src homology 3 domain of Src-Like Adaptor Protein 2; SLAP2 plays a role in c-Cbl-dependent regulation of CSF1R, a tyrosine kinase important for myeloid cell growth and differentiation. It has been shown to interact with CSF1R, c-Cbl, LAT, CD247, and Zap70. SLAPs are adaptor proteins with limited similarity to Src family tyrosine kinases. They contain an N-terminal SH3 domain followed by an SH2 domain, and a unique C-terminal sequence. They function in regulating the signaling, ubiquitination, and trafficking of T-cell receptor (TCR) and B-cell receptor (BCR) components. The SH3 domain of SLAP forms a complex with v-Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212944 Cd Length: 55 Bit Score: 38.57 E-value: 1.29e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNpDWWK--GEVAGVTGLFPTNYV 1125
Cdd:cd12011     1 VAVALCNFPSGGPTELSIRMGEQLTILSEDG-DWWKvsSAVTGRECYIPSNYV 52

Src Homology 3 domain of Apoptosis Stimulating of p53 protein 1; ASPP1, like ASPP2, activates the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73). In addition, it functions in the cytoplasm to regulate the nuclear localization of the transcriptional cofactors YAP and TAZ by inihibiting their phosphorylation; YAP and TAZ are important regulators of cell expansion, differentiation, migration, and invasion. ASPP1 is downregulated in breast tumors expressing wild-type p53. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of ASPP1 contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212887 [Multi-domain] Cd Length: 57 Bit Score: 38.46 E-value: 1.30e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVT----EKEGEWWRGCIGDQTGLFPSN 980
Cdd:cd11954     5 ALWDYEAQNADELSFQEGDAITILrrkdDSETEWWWARLNDKEGYVPKN 53

Src homology 3 domain of Protein arginine N-methyltransferase 2; PRMT2, also called HRMT1L1, belongs to the arginine methyltransferase protein family. It functions as a coactivator to both estrogen receptor alpha (ER-alpha) and androgen receptor (AR), presumably through arginine methylation. The ER-alpha transcription factor is involved in cell proliferation, differentiation, morphogenesis, and apoptosis, and is also implicated in the development and progression of breast cancer. PRMT2 and its variants are upregulated in breast cancer cells and may be involved in modulating the ER-alpha signaling pathway during formation of breast cancer. PRMT2 also plays a role in regulating the function of E2F transcription factors, which are critical cell cycle regulators, by binding to the retinoblastoma gene product (RB). It contains an N-terminal SH3 domain and an AdoMet binding domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212740 [Multi-domain] Cd Length: 53 Bit Score: 38.14 E-value: 1.33e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEKEG-EWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd11806     1 EYVAIADFVATDDSQLSFESGDKLLVLRKPSvDWWWAEHNGCCGYIPASHLHQ 53

Src homology 3 domain of ephexin-1-like SH3 domain containing Rho guanine nucleotide exchange factors; Members of this family contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and C-terminal SH3 domains. They include the Rho guanine nucleotide exchange factors ARHGEF5, ARHGEF16, ARHGEF19, ARHGEF26, ARHGEF27 (also called ephexin-1), and similar proteins, and are also called ephexins because they interact directly with ephrin A receptors. GEFs interact with Rho GTPases via their DH domains to catalyze nucleotide exchange by stabilizing the nucleotide-free GTPase intermediate. They play important roles in neuronal development. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212727 [Multi-domain] Cd Length: 55 Bit Score: 38.47 E-value: 1.35e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146 1003 QVTTVSP--ATTPEQLSLTPGQLIVVLHKNSNSWWLGElqaRGKKRKKGWFQSSNVR 1057
Cdd:cd11793     1 QVQCVHAytAQQPDELTLEEGDVVNVLRKMPDGWYEGE---RLRDGERGWFPSSYTE 54

Fourth Src homology 3 domain (or SH3D) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212773 [Multi-domain] Cd Length: 58 Bit Score: 38.47 E-value: 1.37e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  939 TYESPESGDLTFSAEDVVLVTEKEGE-WWRG-CIGD----QTGLFPSNYVK 983
Cdd:cd11839     7 PFTATAENQLSLAVGQLVLVRKKSPSgWWEGeLQARgkkrQIGWFPANYVK 57

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

Pssm-ID: 443941 [Multi-domain] Cd Length: 1089 Bit Score: 43.37 E-value: 1.46e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  472 KDRKRSLEIELEAVGNKHKQISSQLRDAKSKRQGQWAELELINQRRDVCITDINSLQLQfdemqRQLNQLGPEKQRLADr 551
Cdd:COG4913   609 RAKLAALEAELAELEEELAEAEERLEALEAELDALQERREALQRLAEYSWDEIDVASAE-----REIAELEAELERLDA- 682

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  552 lvhftqniSSPLIndvkqsvcekdrscRKLKEQLDVLEREttaklsqMEQYNKEIKELRQKQSQQQDVLEQLRRVRSDKL 631
Cdd:COG4913   683 --------SSDDL--------------AALEEQLEELEAE-------LEELEEELDELKGEIGRLEKELEQAEEELDELQ 733

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 688602146  632 KELQRHRKEEEERKRKKEEEAARQAqleqerleqeeaerqrkLAQEREAKLRE--EQQRQALARLLEAQEQ 700
Cdd:COG4913   734 DRLEAAEDLARLELRALLEERFAAA-----------------LGDAVERELREnlEERIDALRARLNRAEE 787

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor 2; ASEF2, also called Spermatogenesis-associated protein 13 (SPATA13), is a GEF that localizes with actin at the leading edge of cells and is important in cell migration and adhesion dynamics. GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF2 can activate both Rac 1 and Cdc42, but only Rac1 activation is necessary for increased cell migration and adhesion turnover. Together with APC (adenomatous polyposis coli) and Neurabin2, a scaffold protein that binds F-actin, it is involved in regulating HGF-induced cell migration. ASEF2 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212907 Cd Length: 54 Bit Score: 38.12 E-value: 1.47e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTE-KEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11974     5 ALWDHVTMDDQELAFKAGDVIRVLEaSNKDWWWGRNEDREAWFPASFVR 53

Third (or C-terminal) Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the third SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212714 [Multi-domain] Cd Length: 55 Bit Score: 38.05 E-value: 1.51e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKEGEWWRGCIGDQTGL---FPSNYVKP 984
Cdd:cd11780     2 YRALYSYTPQNEDELELREGDIVYVMEKCDDGWFVGTSERTGLfgtFPGNYVAR 55

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member, Embryonal Fyn-associated Substrate; EFS is also called HEFS, CASS3 (Cas scaffolding protein family member 3) or SIN (Src-interacting protein). It was identified based on interactions with the Src kinases, Fyn and Yes. It plays a role in thymocyte development and acts as a negative regulator of T cell proliferation. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212936 Cd Length: 62 Bit Score: 38.33 E-value: 1.54e-03

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALY--TYESPEsgDLTFSAEDVVLVTEKEGE----WWRGCIGDQTGLFPSNYVK--PKEP 987
Cdd:cd12003     5 ALYdnAAESPE--ELSFRRGDVLMVLKREHGslpgWWLCSLHGQQGIAPANRLRllPTAP 62

Src homology 3 domain of JNK-interacting protein 2; JNK-interacting protein 2 (JIP2) is also called Mitogen-activated protein kinase 8-interacting protein 2 (MAPK8IP2) or Islet-brain-2 (IB2). It is widely expressed in the brain, where it forms complexes with fibroblast growth factor homologous factors (FHFs), which facilitates activation of the p38delta MAPK. JIP2 is enriched in postsynaptic densities and may play a role in motor and cognitive function. In addition to a JNK binding domain, JIP2 also contains SH3 and Phosphotyrosine-binding (PTB) domains. The SH3 domain of the related protein JIP1 homodimerizes at the interface usually involved in proline-rich ligand recognition, despite the lack of this motif in the domain itself. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212875 Cd Length: 55 Bit Score: 38.37 E-value: 1.55e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDEstvRETGWLYGSY---SGNRGWFPESYA 803
Cdd:cd11942     1 THRAVFRFIPRHEDELELDVDDPLLVEA---EEDDYWYRGYnmrTGERGIFPAFYA 53

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; N-terminal SH3 domain of the uncharacterized protein SH3 domain-containing protein 21, and similar uncharacterized domains, it belongs to the CD2AP-like_3 subfamily of proteins. The CD2AP-like_3 subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213018 [Multi-domain] Cd Length: 55 Bit Score: 38.22 E-value: 1.65e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 688602146 1013 PEQLSLTPGQLIVVLHKNS--NSWWLGELQARgkkrkKGWF 1051
Cdd:cd12142    13 PDELALKKGDVIEVISKETedEGWWEGELNGR-----RGFF 48

Calcium binding and coiled-coil domain (CALCOCO1) like; Proteins found in this family are similar to the coiled-coil transcriptional coactivator protein coexpressed by Mus musculus (CoCoA/CALCOCO1). This protein binds to a highly conserved N-terminal domain of p160 coactivators, such as GRIP1, and thus enhances transcriptional activation by a number of nuclear receptors. CALCOCO1 has a central coiled-coil region with three leucine zipper motifs, which is required for its interaction with GRIP1 and may regulate the autonomous transcriptional activation activity of the C-terminal region.

Pssm-ID: 462303 [Multi-domain] Cd Length: 488 Bit Score: 42.96 E-value: 1.78e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   461 KEKEQnDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRQGQWAELELINQrrdvcitDINSLQLQFDEMQRQLNQ 540
Cdd:pfam07888  132 RELEE-DIKTLTQRVLERETELERMKERAKKAGAQRKEEEAERKQLQAKLQQTEE-------ELRSLSKEFQELRNSLAQ 203

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   541 LGPEKQRLADRLVHFTQnisspLINDVKQSVCEKDRSC---RKLKEQLDVLERETTA---KLSQM-EQYNKEIKELRQKQ 613
Cdd:pfam07888  204 RDTQVLQLQDTITTLTQ-----KLTTAHRKEAENEALLeelRSLQERLNASERKVEGlgeELSSMaAQRDRTQAELHQAR 278

                          170
                   ....*....|
gi 688602146   614 SQQQDVLEQL 623
Cdd:pfam07888  279 LQAAQLTLQL 288

Src Homology 3 domain of Cytokinesis protein 3 and similar proteins; Cytokinesis protein 3 (Cyk3 or Cyk3p) is a component of the actomyosin ring independent cytokinesis pathway in yeast. It interacts with Inn1 and facilitates its recruitment to the bud neck, thereby promoting cytokinesis. Cyk3p contains an N-terminal SH3 domain and a C-terminal transglutaminase-like domain. The Cyk3p SH3 domain binds to the C-terminal proline-rich region of Inn1. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212822 Cd Length: 53 Bit Score: 37.86 E-value: 1.83e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEV--AGVTGLFPTNYV 1125
Cdd:cd11889     2 VKAVYSWAGETEGDLGFLEGDLIEVLSIGDGSWWSGKLrrNGAEGIFPSNFV 53

helix-rich Mycoplasma protein; Members of this family occur strictly within a subset of Mycoplasma species. Members average 750 amino acids in length, including signal peptide. Sequences are predicted (Jpred 3) to be almost entirely alpha-helical. These sequences show strong periodicity (consistent with long alpha helical structures) and low complexity rich in D,E,N,Q, and K. Genes encoding these proteins are often found in tandem. The function is unknown.

Pssm-ID: 275316 [Multi-domain] Cd Length: 745 Bit Score: 43.09 E-value: 1.85e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   451 KSKRVELQTQKEKEQNDIQRLKDRKRSLEIEL---EAVGNKHKQISSQLRDAKSKRQGQWAELELINQrrdvcitDINSL 527
Cdd:TIGR04523  172 ENELNLLEKEKLNIQKNIDKIKNKLLKLELLLsnlKKKIQKNKSLESQISELKKQNNQLKDNIEKKQQ-------EINEK 244

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   528 QLQFDEMQRQLNQLGPEKQRLADRLVHFT-----------------QNISSPL--INDVKQSVCEKDrscrkLKEQLDVL 588
Cdd:TIGR04523  245 TTEISNTQTQLNQLKDEQNKIKKQLSEKQkeleqnnkkikelekqlNQLKSEIsdLNNQKEQDWNKE-----LKSELKNQ 319

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   589 ERETTAKLSQMEQYNKEIKELRQKQSQQQDVLEQLRRVRSDKLKELQRHRKEEeerkrkkeeeaarqaqleqerleqeea 668
Cdd:TIGR04523  320 EKKLEEIQNQISQNNKIISQLNEQISQLKKELTNSESENSEKQRELEEKQNEI--------------------------- 372

                          250       260       270
                   ....*....|....*....|....*....|....*...
gi 688602146   669 erqRKLAQEREAKLRE----EQQRQALARLLEAQEQAR 702
Cdd:TIGR04523  373 ---EKLKKENQSYKQEiknlESQINDLESKIQNQEKLN 407

Second Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212696 [Multi-domain] Cd Length: 57 Bit Score: 38.15 E-value: 1.86e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  753 RALYPFTARNSDELTLEADCFIQV---DESTVrETGWLYGSYSGNRGWFP 799
Cdd:cd11762     3 RALYDYEAQSDEELSFPEGAIIRIlrkDDNGV-DDGWWEGEFNGRVGVFP 51

C2 domain present in the putative elicitor-responsive gene; In plants elicitor-responsive proteins are triggered in response to specific elicitor molecules such as glycolproteins, peptides, carbohydrates and lipids. A host of defensive responses are also triggered resulting in localized cell death. Antimicrobial secondary metabolites, such as phytoalexins, or defense-related proteins, including pathogenesis-related (PR) proteins are also produced. There is a single C2 domain present here. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members have a type-II topology.

Pssm-ID: 176014 [Multi-domain] Cd Length: 124 Bit Score: 40.01 E-value: 1.88e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKPCKPNGKSNPYCELTMGAQCYTSRHQPDT-LNPKWSFNCQFFIKDLYQDV---LCLTVFERDQFSP 1586
Cdd:cd04049     1 GTLEVLLISAKGLQDTDFLGKIDPYVIIQCRTQERKSKVAKGDgRNPEWNEKFKFTVEYPGWGGdtkLILRIMDKDNFSD 80

                          90
                  ....*....|.
gi 688602146 1587 DDFLGRTEVPV 1597
Cdd:cd04049    81 DDFIGEATIHL 91

Leucine zipper; This family includes Leucine zipper transcription factor-like protein 1 (LZTFL1) and Leucine zipper protein 2 (LUZP2).

Pssm-ID: 464620 [Multi-domain] Cd Length: 276 Bit Score: 42.00 E-value: 1.91e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   457 LQTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAkskrqgqwaELELINQR-RDVCITDINSLQLQFDEMQ 535
Cdd:pfam15294  131 LHMEIERLKEENEKLKERLKTLESQATQALDEKSKLEKALKDL---------QKEQGAKKdVKSNLKEISDLEEKMAALK 201

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   536 RQLNQlgpekqrladrlvhfTQNISSPLINDVKQSVCEKDRSCRKLKEQLDVLERETTAKLSQMEQY----------NKE 605
Cdd:pfam15294  202 SDLEK---------------TLNASTALQKSLEEDLASTKHELLKVQEQLEMAEKELEKKFQQTAAYrnmkemltkkNEQ 266

                          170
                   ....*....|
gi 688602146   606 IKELRQKQSQ 615
Cdd:pfam15294  267 IKELRKRLSK 276

C2 domain third repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); plant subset; MCTPs are involved in Ca2+ signaling at the membrane. Plant-MCTPs are composed of a variable N-terminal sequence, four C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

Pssm-ID: 175986 [Multi-domain] Cd Length: 150 Bit Score: 40.34 E-value: 1.92e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1513 LLVTVLEATELKPCKPNGKSNPYCELTMGAQCY-TSRHQPDTLNPKWSFNCQFFIKDLYQDVLCLTVFERDQFSPDDFLG 1591
Cdd:cd04019     2 LRVTVIEAQDLVPSDKNRVPEVFVKAQLGNQVLrTRPSQTRNGNPSWNEELMFVAAEPFEDHLILSVEDRVGPNKDEPLG 81

                          90
                  ....*....|....*.
gi 688602146 1592 RTEVPVATIKKDQDGK 1607
Cdd:cd04019    82 RAVIPLNDIERRVDDR 97

C2 domain present in Calpain proteins; A single C2 domain is found in calpains (EC 3.4.22.52, EC 3.4.22.53), calcium-dependent, non-lysosomal cysteine proteases. Caplains are classified as belonging to Clan CA by MEROPS and include six families: C1, C2, C10, C12, C28, and C47. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 176011 [Multi-domain] Cd Length: 126 Bit Score: 39.95 E-value: 1.94e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1515 VTVLEATELKPCKPNGKSNPYCELTMGAQCYTSRHQPDTLNPKWSFNCQFFIKDLYQDVLcLTVFERDQFSpDDFLGRTE 1594
Cdd:cd04046     7 VHVHSAEGLSKQDSGGGADPYVIIKCEGESVRSPVQKDTLSPEFDTQAIFYRKKPRSPIK-IQVWNSNLLC-DEFLGQAT 84


                  ....
gi 688602146 1595 VPVA 1598
Cdd:cd04046    85 LSAD 88

Third Src Homology 3 domain of SH3 domain containing ring finger 1 (SH3RF1), SH3RF3, and similar domains; SH3RF1 (or POSH) and SH3RF3 (or POSH2) are scaffold proteins that function as E3 ubiquitin-protein ligases. They contain an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle of SH3RF1 and SH3RF3, and similar domains. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212717 [Multi-domain] Cd Length: 55 Bit Score: 37.76 E-value: 1.95e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTVreTGWLYGSY--SGNRGWFPESY 802
Cdd:cd11783     2 YVALYPYKPQKPDELELRKGEMYTVTEKCQ--DGWFKGTSlrTGQSGVFPGNY 52

Src Homology 3 domain of SH3 domain and tetratricopeptide repeat-containing (SH3TC) proteins and similar domains; This subfamily is composed of vertebrate SH3TC proteins and hypothetical fungal proteins containing BAR and SH3 domains. Mammals contain two SH3TC proteins, SH3TC1 and SH3TC2. The function of SH3TC1 is unknown. SH3TC2 is localized in Schwann cells in the peripheral nervous system, where it interacts with Rab11 and plays a role in peripheral nerve myelination. Mutations in SH3TC2 are associated with Charcot-Marie-Tooth disease type 4C, a severe hereditary peripheral neuropathy with symptoms that include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212818 Cd Length: 55 Bit Score: 38.07 E-value: 1.98e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLN--KDNPDWWKGEVA--GVTGLFPTNYV 1125
Cdd:cd11885     1 SCTAKMDFEGVEPGELSFRQGDSIEIIGdlIPGLQWFVGRSKssGRVGFVPTNHF 55

Src Homology 3 domain of Saccharomyces cerevisiae Nap1-binding protein 2 and similar fungal proteins; This subfamily includes Saccharomyces cerevisiae Nbp2 (Nucleosome assembly protein 1 (Nap1)-binding protein 2), Schizosaccharomyces pombe Skb5, and similar proteins. Nbp2 interacts with Nap1, which is essential for maintaining proper nucleosome structures in transcription and replication. It is also the binding partner of the yeast type II protein phosphatase Ptc1p and serves as a scaffolding protein that brings seven kinases in close contact to Ptc1p. Nbp2 plays a role many cell processes including organelle inheritance, mating hormone response, cell wall stress, mitotic cell growth at elevated temperatures, and high osmolarity. Skb5 interacts with the p21-activated kinase (PAK) homolog Shk1, which is critical for fission yeast cell viability. Skb5 activates Shk1 and plays a role in regulating cell morphology and growth under hypertonic conditions. Nbp2 and Skb5 contain an SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212799 Cd Length: 55 Bit Score: 37.88 E-value: 2.02e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWW--KGEVAGVTGLFPTNYVKM 1127
Cdd:cd11865     1 RAVALYDFEPEHDNELGFAEGQILFILYKHGQGWLiaEDESGGKTGLVPEEFVSY 55

Predicted nucleic acid-binding protein DR0291, contains C4-type Zn-ribbon domain [General function prediction only];

Pssm-ID: 441187 [Multi-domain] Cd Length: 236 Bit Score: 41.83 E-value: 2.02e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  451 KSKRVELQTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRqgqwaelelinqrrdvcitdinslqlQ 530
Cdd:COG1579    37 EDELAALEARLEAAKTELEDLEKEIKRLELEIEEVEARIKKYEEQLGNVRNNK--------------------------E 90

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  531 FDEMQRQLNQLGPEKQRLADRLVHFTQNIssplinDVKQSVCEKDRScrKLKEQLDVLERETTAKLSQMEQYNKEIKELR 610
Cdd:COG1579    91 YEALQKEIESLKRRISDLEDEILELMERI------EELEEELAELEA--ELAELEAELEEKKAELDEELAELEAELEELE 162

                         170       180
                  ....*....|....*....|....*
gi 688602146  611 QKQSQQ-----QDVLEQLRRVRSDK 630
Cdd:COG1579   163 AEREELaakipPELLALYERIRKRK 187

Pleckstrin homology domain-containing family G member 5 and 6 pleckstrin homology (PH) domain; PLEKHG5 has a RhoGEF DH/double-homology domain in tandem with a PH domain which is involved in phospholipid binding. PLEKHG5 activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in PLEKHG5 are associated with autosomal recessive distal spinal muscular atrophy. PLEKHG6 (also called MyoGEF) has no known function to date. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 270064 Cd Length: 100 Bit Score: 39.13 E-value: 2.06e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1377 RKLLHSG--KLHKTKSSK-ELWALLFNDFLLLTytsKQFSSSPDKlfnpnsntqYKMYKTPVFLNEVLVKMPSDPSSddp 1453
Cdd:cd13244     1 RRLLLEGdlRLKEGKGSKvDVHCFLFTDMLLIC---KPVKRKKDR---------LKVIRPPYLVDKLVVQELKDPGG--- 65

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 688602146 1454 vFHISHIDR------VYTLKTDTINERTTWVQKIK 1482
Cdd:cd13244    66 -FLLVYLNEfhtavaAYTFQTSSQEDTRRWLDAIR 99

Uncharacterized conserved protein YhaN, contains AAA domain [Function unknown];

Pssm-ID: 443752 [Multi-domain] Cd Length: 641 Bit Score: 42.83 E-value: 2.08e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  462 EKEQNDIQRLKDRKRSLEIEleavgnKHKQISSQLRDAKSKrQGQWAELelinqrrdvcITDINSLQLQFDEMQRQLNQL 541
Cdd:COG4717    52 EKEADELFKPQGRKPELNLK------ELKELEEELKEAEEK-EEEYAEL----------QEELEELEEELEELEAELEEL 114

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  542 GPEKQRLadrlvhftqnissplindvkqsvcekdrscRKLKEQLDVLERETTAKlSQMEQYNKEIKELRQKQSQQQDVLE 621
Cdd:COG4717   115 REELEKL------------------------------EKLLQLLPLYQELEALE-AELAELPERLEELEERLEELRELEE 163

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 688602146  622 QLRRvRSDKLKELQRHRKEEEERKRKKEEEAARQAQLEQERLEQEEAERQRKLAQEREAKLREEQQRQALARLLEAQEQ 700
Cdd:COG4717   164 ELEE-LEAELAELQEELEELLEQLSLATEEELQDLAEELEELQQRLAELEEELEEAQEELEELEEELEQLENELEAAAL 241

Src Homology 3 domain of Insulin Receptor tyrosine kinase Substrate p53; IRSp53 is also known as BAIAP2 (Brain-specific Angiogenesis Inhibitor 1-Associated Protein 2). It is a scaffolding protein that takes part in many signaling pathways including Cdc42-induced filopodia formation, Rac-mediated lamellipodia extension, and spine morphogenesis. IRSp53 exists as multiple splicing variants that differ mainly at the C-termini. One variant (T-form) is expressed exclusively in human breast cancer cells. The gene encoding IRSp53 is a putative susceptibility gene for Gilles de la Tourette syndrome. IRSp53 can also mediate the recruitment of effector proteins Tir and EspFu, which regulate host cell actin reorganization, to bacterial attachment sites. It contains an N-terminal IMD, a CRIB (Cdc42 and Rac interactive binding motif), an SH3 domain, and a WASP homology 2 (WH2) actin-binding motif at the C-terminus. The SH3 domain of IRSp53 has been shown to bind the proline-rich C-terminus of EspFu. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212848 Cd Length: 59 Bit Score: 38.07 E-value: 2.21e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 688602146  869 LGFCKDDIITVL--EKQENWWYGELKEK--RGWFPCSHVSVV 906
Cdd:cd11915    18 LSFKEGDYITLLvpEARDGWHYGECEKTkmRGWFPFSYTRVL 59

Src Homology 3 domain of Sdc25/Cdc25 guanine nucleotide exchange factors; This subfamily is composed of the Saccharomyces cerevisiae guanine nucleotide exchange factors (GEFs) Sdc25 and Cdc25, and similar proteins. These GEFs regulate Ras by stimulating the GDP/GTP exchange on Ras. Cdc25 is involved in the Ras/PKA pathway that plays an important role in the regulation of metabolism, stress responses, and proliferation, depending on available nutrients and conditions. Proteins in this subfamily contain an N-terminal SH3 domain as well as REM (Ras exchanger motif) and RasGEF domains at the C-terminus. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212816 Cd Length: 55 Bit Score: 37.65 E-value: 2.22e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDESTvrETGW-----LYGSYSGNRGWFPESY 802
Cdd:cd11883     3 VALYDFTPKSKNQLSFKAGDIIYVLNKD--PSGWwdgviISSSGKVKRGWFPSNY 55

Src Homology 3 domain of the p40phox subunit of NADPH oxidase; p40phox, also called Neutrophil cytosol factor 4 (NCF-4), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p40phox positively regulates NADPH oxidase in both phosphatidylinositol-3-phosphate (PI3P)-dependent and PI3P-independent manner. It contains an N-terminal PX domain, a central SH3 domain, and a C-terminal PB1 domain that interacts with p67phox. The SH3 domain of p40phox binds to canonical polyproline and noncanonical motifs at the C-terminus of p47phox. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212802 Cd Length: 54 Bit Score: 37.86 E-value: 2.30e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVV-LVTEKEGEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11869     4 ALFDFTGNSKLELNFKAGDVIfLLSRVNKDWLEGTVRGATGIFPLSFVK 52

Third Src Homology 3 domain of SH3 domain containing ring finger 2; SH3RF2 is also called POSHER (POSH-eliminating RING protein) or HEPP1 (heart protein phosphatase 1-binding protein). It acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal RING finger domain and three SH3 domains. This model represents the third SH3 domain, located in the middle, of SH3RF2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212718 Cd Length: 55 Bit Score: 37.83 E-value: 2.33e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  934 YVALYTY--ESPESGDLTFSAEDVVLVTEKEGeWWRGC--IGDQTGLFPSNYVKP 984
Cdd:cd11784     2 CVALHSYsaHRPEELELQKGEGVRVLGKFQEG-WLRGLslVTGRVGIFPSNYVSP 55

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6, N-terminal Pleckstrin Homology (PH) domain; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 275424 Cd Length: 124 Bit Score: 39.56 E-value: 2.38e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1377 RKLLHSGKLHKTkSSKEL---WALLFNDFLLltYTSKQFSSSPDKLFN--PNSNTQYKMYKTPVFLNEvlvkmpsdpssd 1451
Cdd:cd13389    12 RKLIKEGELMKV-SRKEMqprYFFLFNDCLL--YTTPVQSSGMLKLNNelPLSGMKVKLPEDEEYSNE------------ 76

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 688602146 1452 dpvFHISHIDRVYTLKTDTINERTTWVQKI-KAASDH 1487
Cdd:cd13389    77 ---FQIISTKRSFTLIASSEEERDEWVKALsRAIEEH 110

Src homology 3 domain of Endophilin-B1; Endophilin-B1, also called Bax-interacting factor 1 (Bif-1) or SH3GLB1 (SH3-domain GRB2-like endophilin B1), is localized mainly to the Golgi apparatus. It is involved in the regulation of many biological events including autophagy, tumorigenesis, nerve growth factor (NGF) trafficking, neurite outgrowth, mitochondrial outer membrane dynamics, and cell death. Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. Endophilin-B1 forms homo- and heterodimers (with endophilin-B2) through its BAR domain. It interacts with amphiphysin 1 and dynamin 1 through its SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212878 Cd Length: 61 Bit Score: 38.08 E-value: 2.40e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146  753 RALYPFTARNSDELTLEADCFIQVDESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11945     7 RVLYDYDAANSTELSLLADEVITVYSVPGMDSDWLMGERGNQKGKVPITYLE 58

First Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the first SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212948 Cd Length: 53 Bit Score: 37.40 E-value: 2.43e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  933 EYVALYTYESPESGDLTFSAEDVVLVTEK-EGEWWRGCIGDQTGLFPSNYVKP 984
Cdd:cd12015     1 QYVVVADYKKQQPNEISLRAGDVVDVIEKnENGWWFVSLEDEQGWVPATYLEP 53

Src Homology 3 domain of Myosin XV; This subfamily is composed of proteins with similarity to Myosin XVa. Myosin XVa is an unconventional myosin that is critical for the normal growth of mechanosensory stereocilia of inner ear hair cells. Mutations in the myosin XVa gene are associated with nonsyndromic hearing loss. Myosin XVa contains a unique N-terminal extension followed by a motor domain, light chain-binding IQ motifs, and a tail consisting of a pair of MyTH4-FERM tandems separated by a SH3 domain, and a PDZ domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212817 [Multi-domain] Cd Length: 56 Bit Score: 37.69 E-value: 2.44e-03

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 688602146  869 LGFCKDDIITVLEKQ----ENWWYGELKEKRGWFPCSHV 903
Cdd:cd11884    16 LSFHKGDVIKLLPKEgpldPGWLFGTLDGRSGAFPKEYV 54

Src Homology 3 domain of Melanoma Inhibitory Activity protein and similar proteins; MIA is a single domain protein that adopts a SH3 domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. MIA is secreted from malignant melanoma cells and it plays an important role in melanoma development and invasion. MIA is expressed by chondrocytes in normal tissues and may be important in the cartilage cell phenotype. Unlike classical SH3 domains, MIA does not bind proline-rich ligands. MIA is a member of the recently identified family that also includes MIA-like (MIAL), MIA2, and MIA3 (also called TANGO); the biological functions of this family are not yet fully understood.

Pssm-ID: 212694 Cd Length: 76 Bit Score: 38.23 E-value: 2.54e-03

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 688602146 1072 PLCQVIAMYDYKAANKDEMSFQKGQLITVLNK---DNPDWWKGEV---AGVTGLFPTNYVK 1126
Cdd:cd11760    10 PISRARALEDYHGPDCRFLNFKKGDTIYVYSKlagERQDLWAGSVggdAGLFGYFPKNLVQ 70

First Src Homology 3 domain (SH3A) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CD2AP. SH3A binds to the PXXXPR motif present in c-Cbl and the cytoplasmic domain of cell adhesion protein CD2. Its interaction with CD2 anchors CD2 at sites of cell contact. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212986 Cd Length: 56 Bit Score: 37.51 E-value: 2.57e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  756 YPFTARNSDELTLEADCFIQvDESTVRETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd12053     6 YDYDAVHEDELTIRVGEIIR-NVKKLEEEGWLEGELNGRRGMFPDNFVK 53

Src homology 3 domain of Rho GTPase-activating proteins 32 and 33, and similar proteins; Members of this family contain N-terminal PX and Src Homology 3 (SH3) domains, a central Rho GAP domain, and C-terminal extensions. RhoGAPs (or ARHGAPs) bind to Rho proteins and enhance the hydrolysis rates of bound GTP. ARHGAP32 is also called RICS, PX-RICS, p250GAP, or p200RhoGAP. It is a Rho GTPase-activating protein for Cdc42 and Rac1, and is implicated in the regulation of postsynaptic signaling and neurite outgrowth. PX-RICS, a variant of RICS that contain PX and SH3 domains, is the main isoform expressed during neural development. It is involved in neural functions including axon and dendrite extension, postnatal remodeling, and fine-tuning of neural circuits during early brain development. ARHGAP33, also called sorting nexin 26 or TCGAP (Tc10/CDC42 GTPase-activating protein), is widely expressed in the brain where it is involved in regulating the outgrowth of axons and dendrites and is regulated by the protein tyrosine kinase Fyn. It is translocated to the plasma membrane in adipocytes in response to insulin and may be involved in the regulation of insulin-stimulated glucose transport. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212769 [Multi-domain] Cd Length: 54 Bit Score: 37.43 E-value: 2.72e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146 1082 YKAANKDEMSFQKGQLITVLNKDNPD---WWKGEVAGVTGLFPTNYV 1125
Cdd:cd11835     8 YTAQAPDELSLEVGDIVSVIDMPPPEestWWRGKKGFQVGFFPSECV 54

Fifth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212752 [Multi-domain] Cd Length: 50 Bit Score: 37.46 E-value: 2.76e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFP 899
Cdd:cd11818     1 KARALYDFTGENEDELSFKAGDIITELESiDEEWMSGELRGKSGIFP 47

Src Homology 3 domain of Brain-specific Angiogenesis Inhibitor 1-Associated Protein 2-Like 1, also called Insulin Receptor Tyrosine Kinase Substrate (IRTKS); BAIAP2L1 or IRTKS is widely expressed, serves as a substrate for the insulin receptor, and binds the small GTPase Rac. It plays a role in regulating the actin cytoskeleton and colocalizes with F-actin, cortactin, VASP, and vinculin. BAIAP2L1 expression leads to the formation of short actin bundles, distinct from filopodia-like protrusions induced by the expression of the related protein IRSp53. IRTKS mediates the recruitment of effector proteins Tir and EspFu, which regulate host cell actin reorganization, to bacterial attachment sites. It contains an N-terminal IMD or Inverse-Bin/Amphiphysin/Rvs (I-BAR) domain, an SH3 domain, and a WASP homology 2 (WH2) actin-binding motif at the C-terminus. The SH3 domain of IRTKS has been shown to bind the proline-rich C-terminus of EspFu. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212846 Cd Length: 58 Bit Score: 37.59 E-value: 2.84e-03

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 688602146  869 LGFCKDDIITVL--EKQENWWYGELK--EKRGWFPCSH 902
Cdd:cd11913    18 LSFAQGDVITLLipEEKDGWLYGEHDttKARGWFPSSY 55

Second Src Homology 3 domain of the fungal endocytic adaptor protein Sla1p; Sla1p facilitates endocytosis by playing a role as an adaptor protein in coupling components of the actin cytoskeleton to the endocytic machinery. It interacts with Abp1p, Las17p and Pan1p, which are activator proteins of actin-related protein 2/3 (Arp2/3). Sla1p contains multiple domains including three SH3 domains, a SAM (sterile alpha motif) domain, and a Sla1 homology domain 1 (SHD1), which binds to the NPFXD motif that is found in many integral membrane proteins such as the Golgi-localized Arf-binding protein Lsb5p and the P4-ATPases, Drs2p and Dnf1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212708 [Multi-domain] Cd Length: 52 Bit Score: 37.44 E-value: 2.85e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLV-TEKEGEW-WRGCIGDQTGLFPSNYV 982
Cdd:cd11774     4 ALYDYDKQTEEELSFNEGDTLDVyDDSDSDWiLVGFNGTQFGFVPANYI 52

C-terminal Src Homology 3 domain of the p67phox subunit of NADPH oxidase and similar proteins; This subfamily is composed of p67phox, NADPH oxidase activator 1 (Noxa1), and similar proteins. p67phox, also called Neutrophil cytosol factor 2 (NCF-2), and Noxa1 are homologs and are the cytosolic subunits of the phagocytic (Nox2) and nonphagocytic (Nox1) NADPH oxidase complexes, respectively. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox and Noxa1 play regulatory roles. p67phox contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. Noxa1 has a similar domain architecture except it is lacking the N-terminal SH3 domain. The TPR domain of both binds activated GTP-bound Rac, while the C-terminal SH3 domain of p67phox and Noxa1 binds the polyproline motif found at the C-terminus of p47phox and Noxo1, respectively. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212803 [Multi-domain] Cd Length: 53 Bit Score: 37.51 E-value: 2.85e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 688602146  854 QAVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHV 903
Cdd:cd11870     1 QVVALHRYEAQGPEDLGFREGDTIDVLSEvNEAWLEGHSDGRVGIFPKCFV 51

Src homology 3 domain of Phospholipase C (PLC) gamma 2; PLCgamma2 is primarily expressed in haematopoietic cells, specifically in B cells. It is activated by tyrosine phosphorylation by B cell receptor (BCR) kinases and is recruited to the plasma membrane where its substrate is located. It is required in pre-BCR signaling and in the maturation of B cells. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212902 Cd Length: 55 Bit Score: 37.51 E-value: 2.85e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQvdeSTVRET-GWLYGSYSGN-RGWFPESYAE 804
Cdd:cd11969     1 TVKALYDYRAKRSDELSFCKGALIH---NVSKETgGWWKGDYGGKvQHYFPSNYVE 53

Src homology 3 domain of ARHGEF9-like Rho guanine nucleotide exchange factors; Members of this family contain a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. They include the Rho guanine nucleotide exchange factors ARHGEF9, ASEF (also called ARHGEF4), ASEF2, and similar proteins. GEFs activate small GTPases by exchanging bound GDP for free GTP. ARHGEF9 specifically activates Cdc42, while both ASEF and ASEF2 can activate Rac1 and Cdc42. ARHGEF9 is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. ASEF plays a role in angiogenesis and cell migration. ASEF2 is important in cell migration and adhesion dynamics. ASEF exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli), leading to the activation of Rac1 or Cdc42. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212762 [Multi-domain] Cd Length: 53 Bit Score: 37.36 E-value: 2.92e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 688602146 1013 PEQLSLTPGQLIVVLHKNSNSWWLGELQARgkkrkKGWFQSSNVRL 1058
Cdd:cd11828    13 PEELGFKAGDVIEVLDMSDKDWWWGSIRDE-----EGWFPASFVRL 53

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213017 [Multi-domain] Cd Length: 57 Bit Score: 37.48 E-value: 2.98e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQV----DESTVREtgWLYGSYSGNRGWFPESY 802
Cdd:cd12141     1 VYYAVYTFKARSPNELSVSANQRVRIlefsDLTGNKE--WWLAEANGQKGYVPSNY 54

Second or C-terminal Src homology 3 domain of NADPH oxidase (Nox) Organizing protein 1; Nox Organizing protein 1 (NoxO1) is a critical regulator of enzyme kinetics of the nonphagocytic NADPH oxidase Nox1, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Nox1 is expressed in colon, stomach, uterus, prostate, and vascular smooth muscle cells. NoxO1 is involved in targeting activator subunits (such as NoxA1) to Nox1. It is co-localized with Nox1 in the membranes of resting cells and directs the subcellular localization of Nox1. NoxO1 contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), and a C-terminal proline-rich region (PRR). This model characterizes the second SH3 domain (or C-SH3) of NoxO1. The tandem SH3 domains of NoxO1 interact with the PRR of p22phox, which also complexes with Nox1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212957 Cd Length: 53 Bit Score: 37.32 E-value: 3.01e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYVK 1126
Cdd:cd12024     4 ATRAYEAQKEDELSVPAGVVVEVLQKSDNGWWLIRYNGRAGYVPSMYLQ 52

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212746 [Multi-domain] Cd Length: 52 Bit Score: 37.11 E-value: 3.05e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146 1010 ATTPEQLSLTPGQLIVVLHKNSNSWWLGELqARGkkrKKGWFQSSNV 1056
Cdd:cd11812    10 ANRSDELTIHRGDIIRVLYKDNDNWWFGSL-VNG---QQGYFPANYV 52

Second Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the second SH3 domain, located C-terminal of the first SH3 domain at the N-terminal half, of SH3RF3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212864 Cd Length: 55 Bit Score: 37.21 E-value: 3.13e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1078 AMYDYKAANKDE----MSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNYV 1125
Cdd:cd11931     4 ALYDFEIKDKDQdkdcLTFTKDEILTVIRRVDENWAEGMLGDKIGIFPILYV 55

Exopolysaccharide export protein/domain GumC/Wzc1 [Cell wall/membrane/envelope biogenesis];

Pssm-ID: 442439 [Multi-domain] Cd Length: 687 Bit Score: 42.31 E-value: 3.30e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  445 RRREWEKSKRVELQTQKEKEQNDIQRLKDRKRSLEIELEA--VGNKHKQISSQLRDAKSKRQGQWAELELINQRRDVCIT 522
Cdd:COG3206   175 KALEFLEEQLPELRKELEEAEAALEEFRQKNGLVDLSEEAklLLQQLSELESQLAEARAELAEAEARLAALRAQLGSGPD 254

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  523 DINSLQ--LQFDEMQRQLNQLgpeKQRLADRLVHFTQNisSPLINDVKQSVcekdrscRKLKEQLDVLERETTAKL-SQM 599
Cdd:COG3206   255 ALPELLqsPVIQQLRAQLAEL---EAELAELSARYTPN--HPDVIALRAQI-------AALRAQLQQEAQRILASLeAEL 322

                         170       180       190
                  ....*....|....*....|....*....|....*..
gi 688602146  600 EQYNKEIKELRQKQSQQQDVLEQLRRVRSdKLKELQR 636
Cdd:COG3206   323 EALQAREASLQAQLAQLEARLAELPELEA-ELRRLER 358

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

Pssm-ID: 274008 [Multi-domain] Cd Length: 1179 Bit Score: 42.35 E-value: 3.31e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   452 SKRVELQTQKEKEQNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRQGQWAELELINQRRDVCITDINSLQLQF 531
Cdd:TIGR02168  670 SSILERRREIEELEEKIEELEEKIAELEKALAELRKELEELEEELEQLRKELEELSRQISALRKDLARLEAEVEQLEERI 749

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   532 DEMQRQLNQLGPEKQRLADRLvhftqNISSPLINDVKQSVCEKDRSCRKLKEQLDVLERETTAKlsqmeqyNKEIKELRQ 611
Cdd:TIGR02168  750 AQLSKELTELEAEIEELEERL-----EEAEEELAEAEAEIEELEAQIEQLKEELKALREALDEL-------RAELTLLNE 817

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   612 KQSQQQDVLEQLRRVRSDKLKELQRhrkeeeerkrkkeeeaarqaqleqerleqeeaerqrklaQEREAKLREEQQRQAL 691
Cdd:TIGR02168  818 EAANLRERLESLERRIAATERRLED---------------------------------------LEEQIEELSEDIESLA 858


                   ....*....
gi 688602146   692 ARLLEAQEQ 700
Cdd:TIGR02168  859 AEIEELEEL 867

Third (or C-terminal) Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212850 [Multi-domain] Cd Length: 61 Bit Score: 37.28 E-value: 3.47e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNR--GWFPESYAER 805
Cdd:cd11917     7 FQALYNYMPRNEDELELREGDVIDVMEKC--DDGWFVGTSRRTKffGTFPGNYVKR 60

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing protein 3 (Stac3); Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212919 [Multi-domain] Cd Length: 53 Bit Score: 37.20 E-value: 3.54e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLE-KQENWWYGELKEKRGWFPCSHV 903
Cdd:cd11986     3 VALYRFKALEKDDLDFHPGERITVIDdSNEEWWRGKIGEKTGYFPMNFI 51

Src homology 3 domain of Abl Interactor proteins; Abl interactor (Abi) proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. They localize to sites of actin polymerization in epithelial adherens junction and immune synapses, as well as to the leading edge of lamellipodia. Vertebrates contain two Abi proteins, Abi1 and Abi2. Abi1 displays a wide expression pattern while Abi2 is highly expressed in the eye and brain. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212760 [Multi-domain] Cd Length: 52 Bit Score: 36.92 E-value: 3.54e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLEKQEN-WWYGELKEKRGWFPCSHV 903
Cdd:cd11826     3 VALYDYTADKDDELSFQEGDIIYVTKKNDDgWYEGVLNGVTGLFPGNYV 51

Second Src Homology 3 domain of Bud emergence protein 1 and similar domains; Members of this subfamily bear similarity to Saccharomyces cerevisiae Bem1p, containing two Src Homology 3 (SH3) domains at the N-terminus, a central PX domain, and a C-terminal PB1 domain. Bem1p is a scaffolding protein that is critical for proper Cdc42p activation during bud formation in yeast. During budding and mating, Bem1p migrates to the plasma membrane where it can serve as an adaptor for Cdc42p and some other proteins. Bem1p also functions as an effector of the G1 cyclin Cln3p and the cyclin-dependent kinase Cdc28p in promoting vacuolar fusion. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212812 [Multi-domain] Cd Length: 56 Bit Score: 37.31 E-value: 3.60e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1077 IAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKG---EVAGVTGLFPTNYV 1125
Cdd:cd11879     3 IVLYDFKAERPDELDAKAGDAIIICAHSNYEWFVAkpiGRLGGPGLIPVSFV 54

Fourth Src homology 3 domain (or SH3D) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212773 [Multi-domain] Cd Length: 58 Bit Score: 37.32 E-value: 3.66e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  863 AKTDSHLGFCKDDIITVLEKQEN-WWYGEL----KEKR-GWFPCSHVSV 905
Cdd:cd11839    10 ATAENQLSLAVGQLVLVRKKSPSgWWEGELqargKKRQiGWFPANYVKL 58

Second Src Homology 3 domain of SH3 domain containing ring finger proteins; This model represents the second SH3 domain of SH3RF1 (or POSH), SH3RF2 (or POSHER), SH3RF3 (POSH2), and similar domains. Members of this family are scaffold proteins that function as E3 ubiquitin-protein ligases. They all contain an N-terminal RING finger domain and multiple SH3 domains; SH3RF1 and SH3RF3 have four SH3 domains while SH3RF2 has three. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3RF2 acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212721 [Multi-domain] Cd Length: 53 Bit Score: 36.93 E-value: 3.71e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  936 ALYTYESPESGD---LTFSAEDVVLVTEKEGE-WWRGCIGDQTGLFPSNY 981
Cdd:cd11787     4 ALYDFEMKDEDEkdcLTFKKGDVITVIRRVDEnWAEGRLGDKIGIFPISF 53

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing proteins; ASAPs are Arf GTPase activating proteins (GAPs) and they function in regulating cell growth, migration, and invasion. They contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. Vertebrates contain at least three members, ASAP1, ASAP2, and ASAP3, but some ASAP3 proteins do not seem to harbor a C-terminal SH3 domain. ASAP1 and ASAP2 show GTPase activating protein (GAP) activity towards Arf1 and Arf5. They do not show GAP activity towards Arf6, but are able to mediate Arf6 signaling by binding stably to GTP-Arf6. ASAP3 is an Arf6-specific GAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212755 [Multi-domain] Cd Length: 53 Bit Score: 36.91 E-value: 3.72e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 688602146 1010 ATTPEQLSLTPGQLIVVLHKNSNSWWLGELQarGKKRKKGWFQSS 1054
Cdd:cd11821    10 ADNDDELTFSEGEIIVVTGEEDDEWWEGHIE--GDPSRRGVFPVS 52

Src Homology 3 domain of Insulin Receptor tyrosine kinase Substrate p53, Brain-specific Angiogenesis Inhibitor 1-Associated Protein 2 (BAIAP2)-Like proteins, and similar proteins; Proteins in this family include IRSp53, BAIAP2L1, BAIAP2L2, and similar proteins. They all contain an Inverse-Bin/Amphiphysin/Rvs (I-BAR) or IMD domain in addition to the SH3 domain. IRSp53, also known as BAIAP2, is a scaffolding protein that takes part in many signaling pathways including Cdc42-induced filopodia formation, Rac-mediated lamellipodia extension, and spine morphogenesis. IRSp53 exists as multiple splicing variants that differ mainly at the C-termini. BAIAP2L1, also called IRTKS (Insulin Receptor Tyrosine Kinase Substrate), serves as a substrate for the insulin receptor and binds the small GTPase Rac. It plays a role in regulating the actin cytoskeleton and colocalizes with F-actin, cortactin, VASP, and vinculin. IRSp53 and IRTKS also mediate the recruitment of effector proteins Tir and EspFu, which regulate host cell actin reorganization, to bacterial attachment sites. BAIAP2L2 co-localizes with clathrin plaques but its function has not been determined. The SH3 domains of IRSp53 and IRTKS have been shown to bind the proline-rich C-terminus of EspFu. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212713 [Multi-domain] Cd Length: 57 Bit Score: 37.30 E-value: 3.87e-03

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 688602146  869 LGFCKDDIITVL--EKQENWWYGEL--KEKRGWFPCSHV 903
Cdd:cd11779    17 LSFEEGDVITLLgpEPRDGWHYGENerSGRRGWFPIAYT 55

First Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the first SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212948 Cd Length: 53 Bit Score: 37.01 E-value: 3.90e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNY 1124
Cdd:cd12015     1 QYVVVADYKKQQPNEISLRAGDVVDVIEKNENGWWFVSLEDEQGWVPATY 50

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

Pssm-ID: 443941 [Multi-domain] Cd Length: 1089 Bit Score: 42.21 E-value: 3.92e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  452 SKRVELQTQKEKEQNDIQRLKDRKRSLEIELEAV-GNKHKQISSQLRDAKskrqgqwAELELINQRRDVCITDINSLQLQ 530
Cdd:COG4913   302 AELARLEAELERLEARLDALREELDELEAQIRGNgGDRLEQLEREIERLE-------RELEERERRRARLEALLAALGLP 374

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  531 FDEMQRQLNQLgpekQRLADRLVHFTQNISSPLINDVKQSVCEKdrscRKLKEQLDVLERettaklsqmeqynkEIKELR 610
Cdd:COG4913   375 LPASAEEFAAL----RAEAAALLEALEEELEALEEALAEAEAAL----RDLRRELRELEA--------------EIASLE 432

                         170
                  ....*....|....*....
gi 688602146  611 QKQS----QQQDVLEQLRR 625
Cdd:COG4913   433 RRKSnipaRLLALRDALAE 451

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212746 [Multi-domain] Cd Length: 52 Bit Score: 37.11 E-value: 4.01e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQV---DESTvretgWLYGSY-SGNRGWFPESY 802
Cdd:cd11812     1 TVVALYDYTANRSDELTIHRGDIIRVlykDNDN-----WWFGSLvNGQQGYFPANY 51

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

Pssm-ID: 274008 [Multi-domain] Cd Length: 1179 Bit Score: 41.97 E-value: 4.09e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   565 NDVKQSVCEKDRSCRKLKEQLDVLERETTAKlsqmeqyNKEIKELRQKQSQQQDVLEQLRRVRSDKLKEL--QRHRKEEE 642
Cdd:TIGR02168  666 AKTNSSILERRREIEELEEKIEELEEKIAEL-------EKALAELRKELEELEEELEQLRKELEELSRQIsaLRKDLARL 738

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 688602146   643 ERKRKKEEEAARQAQLEQERLEQEEAERQRKLAQEREAKLREEQQRQALARLLEAQEQ 700
Cdd:TIGR02168  739 EAEVEQLEERIAQLSKELTELEAEIEELEERLEEAEEELAEAEAEIEELEAQIEQLKE 796

C2 domain second repeat in Munc13 (mammalian uncoordinated)-like proteins; C2-like domains are thought to be involved in phospholipid binding in a Ca2+ independent manner in both Unc13 and Munc13. Caenorabditis elegans Unc13 has a central domain with sequence similarity to PKC, which includes C1 and C2-related domains. Unc13 binds phorbol esters and DAG with high affinity in a phospholipid manner. Mutations in Unc13 results in abnormal neuronal connections and impairment in cholinergic neurotransmission in the nematode. Munc13 is the mammalian homolog which are expressed in the brain. There are 3 isoforms (Munc13-1, -2, -3) and are thought to play a role in neurotransmitter release and are hypothesized to be high-affinity receptors for phorbol esters. Unc13 and Munc13 contain both C1 and C2 domains. There are two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. Munc13 interacts with syntaxin, synaptobrevin, and synaptotagmin suggesting a role for these as scaffolding proteins. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

Pssm-ID: 175976 [Multi-domain] Cd Length: 133 Bit Score: 39.14 E-value: 4.11e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1500 YQARSQKnsgigrLLVTVLEATELKPCKPNGKSNPYCELTM-------GAQCYTSRHQPDTLNP----KWSFN-----CQ 1563
Cdd:cd04009    11 YRASEQS------LRVEILNARNLLPLDSNGSSDPFVKVELlprhlfpDVPTPKTQVKKKTLFPlfdeSFEFNvppeqCS 84

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 688602146 1564 ffikdLYQDVLCLTVFERDQFSPDDFLGRTEVPVATIKKDQDGKGP 1609
Cdd:cd04009    85 -----VEGALLLFTVKDYDLLGSNDFEGEAFLPLNDIPGVEDTSSA 125

helix-rich Mycoplasma protein; Members of this family occur strictly within a subset of Mycoplasma species. Members average 750 amino acids in length, including signal peptide. Sequences are predicted (Jpred 3) to be almost entirely alpha-helical. These sequences show strong periodicity (consistent with long alpha helical structures) and low complexity rich in D,E,N,Q, and K. Genes encoding these proteins are often found in tandem. The function is unknown.

Pssm-ID: 275316 [Multi-domain] Cd Length: 745 Bit Score: 41.93 E-value: 4.15e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   451 KSKRVELQT-QKEKEQ--NDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSkrqgqwaELELINQRRDVCITDINSL 527
Cdd:TIGR04523  366 EEKQNEIEKlKKENQSykQEIKNLESQINDLESKIQNQEKLNQQKDEQIKKLQQ-------EKELLEKEIERLKETIIKN 438

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   528 QLQFDEMQRQLNQLGPEKQRLADRLVHFTQNIS--SPLINDVKQSVCEKDRSC--------------RKLKEQLDVLERE 591
Cdd:TIGR04523  439 NSEIKDLTNQDSVKELIIKNLDNTRESLETQLKvlSRSINKIKQNLEQKQKELkskekelkklneekKELEEKVKDLTKK 518

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|...
gi 688602146   592 TTAKLSQMEQYNKEIKELRQKQSQQQDVLEQLR-RVRSDKLKE 633
Cdd:TIGR04523  519 ISSLKEKIEKLESEKKEKESKISDLEDELNKDDfELKKENLEK 561

Src Homology 3 domain of Insulin Receptor tyrosine kinase Substrate p53, Brain-specific Angiogenesis Inhibitor 1-Associated Protein 2 (BAIAP2)-Like proteins, and similar proteins; Proteins in this family include IRSp53, BAIAP2L1, BAIAP2L2, and similar proteins. They all contain an Inverse-Bin/Amphiphysin/Rvs (I-BAR) or IMD domain in addition to the SH3 domain. IRSp53, also known as BAIAP2, is a scaffolding protein that takes part in many signaling pathways including Cdc42-induced filopodia formation, Rac-mediated lamellipodia extension, and spine morphogenesis. IRSp53 exists as multiple splicing variants that differ mainly at the C-termini. BAIAP2L1, also called IRTKS (Insulin Receptor Tyrosine Kinase Substrate), serves as a substrate for the insulin receptor and binds the small GTPase Rac. It plays a role in regulating the actin cytoskeleton and colocalizes with F-actin, cortactin, VASP, and vinculin. IRSp53 and IRTKS also mediate the recruitment of effector proteins Tir and EspFu, which regulate host cell actin reorganization, to bacterial attachment sites. BAIAP2L2 co-localizes with clathrin plaques but its function has not been determined. The SH3 domains of IRSp53 and IRTKS have been shown to bind the proline-rich C-terminus of EspFu. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212713 [Multi-domain] Cd Length: 57 Bit Score: 36.92 E-value: 4.27e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146 1075 QVIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWW---KGEVAGVTGLFPTNYVK 1126
Cdd:cd11779     2 RVKALYPHAAGGETQLSFEEGDVITLLGPEPRDGWhygENERSGRRGWFPIAYTE 56

Src homology 3 domain of Endophilin-B; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain two endophilin-B isoforms. Endophilin-B proteins are cytoplasmic proteins expressed mainly in the heart, placenta, and skeletal muscle. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212736 [Multi-domain] Cd Length: 52 Bit Score: 36.88 E-value: 4.29e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1078 AMYDYKAANKDEMSFQKGQLITVLNKD--NPDWWKGEVAGVTGLFPTNY 1124
Cdd:cd11802     4 VLYDYDAEDSTELSLLADEVITVYELPgmDEDYMMGERGSQRGKVPVAY 52

Src Homology 3 domain of Brain-specific Angiogenesis Inhibitor 1-Associated Protein 2-Like 1, also called Insulin Receptor Tyrosine Kinase Substrate (IRTKS); BAIAP2L1 or IRTKS is widely expressed, serves as a substrate for the insulin receptor, and binds the small GTPase Rac. It plays a role in regulating the actin cytoskeleton and colocalizes with F-actin, cortactin, VASP, and vinculin. BAIAP2L1 expression leads to the formation of short actin bundles, distinct from filopodia-like protrusions induced by the expression of the related protein IRSp53. IRTKS mediates the recruitment of effector proteins Tir and EspFu, which regulate host cell actin reorganization, to bacterial attachment sites. It contains an N-terminal IMD or Inverse-Bin/Amphiphysin/Rvs (I-BAR) domain, an SH3 domain, and a WASP homology 2 (WH2) actin-binding motif at the C-terminus. The SH3 domain of IRTKS has been shown to bind the proline-rich C-terminus of EspFu. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212846 Cd Length: 58 Bit Score: 37.20 E-value: 4.38e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 688602146  753 RALYPFTARNSDELTleadCFIQVDESTV----RETGWLYGSY--SGNRGWFPESY 802
Cdd:cd11913     4 KTIFPHTAGNNKTLL----SFAQGDVITLlipeEKDGWLYGEHdtTKARGWFPSSY 55

flagellar export protein FliJ; Members of this family are the FliJ protein found, in nearly every case, in the midst of other flagellar biosynthesis genes in bacgterial genomes. Typically the fliJ gene is found adjacent to the gene for the flagellum-specific ATPase FliI. Sequence scoring in the gray zone between trusted and noise cutoffs include both probable FliJ proteins and components of bacterial type III secretion systems.

Pssm-ID: 131526 [Multi-domain] Cd Length: 141 Bit Score: 39.22 E-value: 4.52e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   510 LELINQRRDVCITDINSLQLQFDEMQRQLNQLGPEKQRLADRLVHFTQN-ISSPLINDVKQSVCEKDRSCRKLKEQLDVL 588
Cdd:TIGR02473    8 LDLREKEEEQAKLELAKAQAEFERLETQLQQLIKYREEYEQQALEKVGAgTSALELSNYQRFIRQLDQRIQQQQQELALL 87

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 688602146   589 ERETTAKLSQMEQYNKEIK---ELRQKQSQQQDVLEQLR 624
Cdd:TIGR02473   88 QQEVEAKRERLLEARRELKaleKLKEKKQKEYRAEEAKR 126

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 37.14 E-value: 4.52e-03

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 688602146  224 KYRQLFNSLDKLMSGYLSGPQVRNALTA--SNLTQTQLATIWFLADVDRDGQLRAEEFILAMH 284
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSlgEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

Src Homology 3 domain of Mixed Lineage Kinases 1, 2, and 3; MLKs 1, 2, and 3 are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Little is known about the specific function of MLK1, also called MAP3K9. It is capable of activating the c-Jun N-terminal kinase pathway. Mice lacking both MLK1 and MLK2 are viable, fertile, and have normal life spans. MLK2, also called MAP3K10, is abundant in brain, skeletal muscle, and testis. It functions upstream of the MAPK, c-Jun N-terminal kinase. It binds hippocalcin, a calcium-sensor protein that protects neurons against calcium-induced cell death. Both MLK2 and hippocalcin may be associated with the pathogenesis of Parkinson's disease. MLK3, also called MAP3K11, is highly expressed in breast cancer cells and its signaling through c-Jun N-terminal kinase has been implicated in the migration, invasion, and malignancy of cancer cells. It also functions as a negative regulator of Inhibitor of Nuclear Factor-KappaB Kinase (IKK) and thus, impacts inflammation and immunity. MLKs contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212992 [Multi-domain] Cd Length: 58 Bit Score: 37.05 E-value: 4.53e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  857 ALCEWSAKTDSHLGFCKDDIITVLEKQ------ENWWYGELKEKRGWFPCSHVS 904
Cdd:cd12059     4 AVFDYEASAEDELTLRRGDRVEVLSKDsavsgdEGWWTGKINDRVGIFPSNYVT 57

Second Src Homology 3 domain (SH3B) of CD2-associated protein and similar proteins; This subfamily is composed of the second SH3 domain (SH3B) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3B of both proteins have been shown to bind to Cbl. In the case of CD2AP, its SH3B binds to Cbl at a site distinct from the c-Cbl/SH3A binding site. The CIN85 SH3B also binds ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212807 [Multi-domain] Cd Length: 53 Bit Score: 36.93 E-value: 4.70e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  753 RALYPFTARNSDELTLEADCFIQV-DEStvrETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11874     3 KVLFSYTPQNEDELELKVGDTIEVlGEV---EEGWWEGKLNGKVGVFPSNFVK 52

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 429575 [Multi-domain] Cd Length: 54 Bit Score: 36.81 E-value: 4.81e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 688602146   752 YRALYPFTARNSDELTLEADCFIQVDEstVRETGWLYGSYSGNRGWFPESY 802
Cdd:pfam07653    2 GRVIFDYVGTDKNGLTLKKGDVVKVLG--KDNDGWWEGETGGRVGLVPSTA 50

Rho guanine nucleotide exchange factor Pleckstrin homology domain; RhoGEFs belongs to regulator of G-protein signaling (RGS) domain-containing RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. The members here all contain Dbl homology (DH)-PH domains. In addition some members contain N-terminal C1 (Protein kinase C conserved region 1) domains, PDZ (also called DHR/Dlg homologous regions) domains, ANK (ankyrin) domains, and RGS (Regulator of G-protein signalling) domains or C-terminal ATP-synthase B subunit. The DH-PH domains bind and catalyze the exchange of GDP for GTP on RhoA. RhoGEF2/Rho guanine nucleotide exchange factor 2, p114RhoGEF/p114 Rho guanine nucleotide exchange factor, p115RhoGEF, p190RhoGEF, PRG/PDZ Rho guanine nucleotide exchange factor, RhoGEF 11, RhoGEF 12, RhoGEF 18, AKAP13/A-kinase anchoring protein 13, and LARG/Leukemia-associated Rho guanine nucleotide exchange factor are included in this CD. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 275411 Cd Length: 109 Bit Score: 38.40 E-value: 4.83e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1379 LLHSGKLH---KTKSSKELWALLFNDFLLLtytskqFSSSPDKLFNPNSNTQYKMYKTP----VFLNEVLVKmpsdPSSD 1451
Cdd:cd13329     1 LIHEGPLTwkvARGKLIEVHVLLLEDLLVL------LQKQDDKYLLKLHLTGSFDSKDTkspvIKLSTLLVR----EVAT 70

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 688602146 1452 DP--VFHISHIDR---VYTLKTDTINERTTWVQKIKAA 1484
Cdd:cd13329    71 DKkaFFLISTSKNgpqMYELVANSSSERKTWIKHISDA 108

chromosome segregation protein SMC, primarily archaeal type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. It is found in a single copy and is homodimeric in prokaryotes, but six paralogs (excluded from this family) are found in eukarotes, where SMC proteins are heterodimeric. This family represents the SMC protein of archaea and a few bacteria (Aquifex, Synechocystis, etc); the SMC of other bacteria is described by TIGR02168. The N- and C-terminal domains of this protein are well conserved, but the central hinge region is skewed in composition and highly divergent. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

Pssm-ID: 274009 [Multi-domain] Cd Length: 1164 Bit Score: 41.59 E-value: 4.92e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   443 RQRRREWekSKRVELQTQKEKEQNDIQRLKDRKRSLEIELEavgnkhkQISSQLRDAKSKRQGQWAElelinqrrdvcit 522
Cdd:TIGR02169  237 RQKEAIE--RQLASLEEELEKLTEEISELEKRLEEIEQLLE-------ELNKKIKDLGEEEQLRVKE------------- 294

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   523 DINSLQLQFDEMQRQLNQLGPEKQRLADRLVHFTQNISSPL--INDVKQSVCEKDRSCRKLKEQLDVLERETTAKLSQME 600
Cdd:TIGR02169  295 KIGELEAEIASLERSIAEKERELEDAEERLAKLEAEIDKLLaeIEELEREIEEERKRRDKLTEEYAELKEELEDLRAELE 374

                          170       180       190
                   ....*....|....*....|....*....|....*.
gi 688602146   601 QYNKEIKELRQKQSQQQDVLEQLRRVRSDKLKELQR 636
Cdd:TIGR02169  375 EVDKEFAETRDELKDYREKLEKLKREINELKRELDR 410

Src Homology 3 domain of Tec (Tyrosine kinase expressed in hepatocellular carcinoma); Tec is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. It is more widely-expressed than other Tec subfamily kinases. Tec is found in endothelial cells, both B- and T-cells, and a variety of myeloid cells including mast cells, erythroid cells, platelets, macrophages and neutrophils. Tec is a key component of T-cell receptor (TCR) signaling, and is important in TCR-stimulated proliferation, IL-2 production and phospholipase C-gamma1 activation. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212838 [Multi-domain] Cd Length: 56 Bit Score: 36.72 E-value: 4.92e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  935 VALYTYESPESGDLTF-SAEDVVLVTEKEGEWW--RGCIGDQtGLFPSNYVKPK 985
Cdd:cd11905     4 VAMYDFQPTEPHDLRLeTGEEYVILEKNDVHWWkaRDKYGKE-GYIPSNYVTGK 56

Coiled-coil domain-containing protein 22; Human coiled-coil domain-containing protein 22 (CCDC22) is involved in regulation of NF-kappa-B signalling; the function may involve association with COMMD8 and a CUL1-dependent E3 ubiquitin ligase complex. It is part of the OMMD/CCDC22/CCDC93 (CCC) complex, which interacts with the multisubunit WASH complex required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. This entry also includes CCDC22 homologs from animals and plants.

Pssm-ID: 461708 [Multi-domain] Cd Length: 600 Bit Score: 41.55 E-value: 5.07e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   456 ELQTQKEKE----QNDIQRLKDRKRSLEIELEAVGNKHKQISSQLRDAKSKRqgqwAELELINQRRDVCI-----TDINS 526
Cdd:pfam05667  328 ELQQQREEEleelQEQLEDLESSIQELEKEIKKLESSIKQVEEELEELKEQN----EELEKQYKVKKKTLdllpdAEENI 403

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   527 LQLQ--FDEMQRQLNQLGP--EKQRladrlvhftqnisSPLINDVkqsvcekdrscRKLKEQLDVLERETTAKLSQMEQY 602
Cdd:pfam05667  404 AKLQalVDASAQRLVELAGqwEKHR-------------VPLIEEY-----------RALKEAKSNKEDESQRKLEEIKEL 459

                          170       180       190
                   ....*....|....*....|....*....|..
gi 688602146   603 NKEIK----ELRQKQSQQQDVLEQLRRVRSDK 630
Cdd:pfam05667  460 REKIKevaeEAKQKEELYKQLVAEYERLPKDV 491

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213017 [Multi-domain] Cd Length: 57 Bit Score: 36.71 E-value: 5.23e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  934 YVALYTYESPESGDLTFSAEDVVLVTEKE-----GEWWRGCIGDQTGLFPSNYVK 983
Cdd:cd12141     2 YYAVYTFKARSPNELSVSANQRVRILEFSdltgnKEWWLAEANGQKGYVPSNYIR 56

Src Homology 3 domain of Sorting nexin 9; Sorting nexin 9 (SNX9), also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization. SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX9 also contains BAR and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212831 Cd Length: 57 Bit Score: 36.76 E-value: 5.40e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688602146 1079 MYDYKA-ANKDEMSFQKGQLITVLNKD-NPDWWKGEVA-GVTGLFPTNYVKM 1127
Cdd:cd11898     5 LYDFAAePGNNELTVKEGEIITVTNPNvGGGWIEAKNSqGERGLVPTDYVEI 56

C2 domain second repeat present in Synaptotagmin 1; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 1, a member of the class 1 synaptotagmins, is located in the brain and endocranium and localized to the synaptic vesicles and secretory granules. It functions as a Ca2+ sensor for fast exocytosis. It, like synaptotagmin-2, has an N-glycosylated N-terminus. Synaptotagmin 4, a member of class 4 synaptotagmins, is located in the brain. It functions are unknown. It, like synaptotagmin-11, has an Asp to Ser substitution in its C2A domain. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 176047 [Multi-domain] Cd Length: 136 Bit Score: 38.92 E-value: 5.51e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146 1511 GRLLVTVLEATELKPCKPNGKSNPYCE--LTMGAQCY----TSRhQPDTLNPKWSFNCQFFIK-DLYQDV-LCLTVFERD 1582
Cdd:cd08402    15 GKLTVVILEAKNLKKMDVGGLSDPYVKihLMQNGKRLkkkkTTI-KKRTLNPYYNESFSFEVPfEQIQKVhLIVTVLDYD 93

                          90
                  ....*....|
gi 688602146 1583 QFSPDDFLGR 1592
Cdd:cd08402    94 RIGKNDPIGK 103

Fourth N-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin and key regulatory proteins of the actin cytoskeleton. It plays an important role in regulating cell junction configuration. The four N-terminal SH3 domains of DNMBP bind the GTPase dynamin, which plays an important role in the fission of endocytic vesicles. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212731 Cd Length: 50 Bit Score: 36.63 E-value: 5.61e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFP 1121
Cdd:cd11797     2 GVALYRFQALEPNELDFEVGDRIRIIATLEDGWLEGELKGRRGIFP 47

Fourth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212751 [Multi-domain] Cd Length: 50 Bit Score: 36.30 E-value: 5.91e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLEKQE-NWWYGELKEKRGWFP 899
Cdd:cd11817     2 AVALYDFTGETEEDLSFQRGDRILVTEHLDaEWSRGRLNGREGIFP 47

Src homology 3 domain of RUN and SH3 domain-containing proteins 1 and 2; RUSC1 and RUSC2, that were originally characterized in silico. They are adaptor proteins consisting of RUN, leucine zipper, and SH3 domains. RUSC1, also called NESCA (New molecule containing SH3 at the carboxy-terminus), is highly expressed in the brain and is translocated to the nuclear membrane from the cytoplasm upon stimulation with neurotrophin. It plays a role in facilitating neurotrophin-dependent neurite outgrowth. It also interacts with NEMO (or IKKgamma) and may function in NEMO-mediated activation of NF-kB. RUSC2, also called Iporin, is expressed ubiquitously with highest amounts in the brain and testis. It interacts with the small GTPase Rab1 and the Golgi matrix protein GM130, and may function in linking GTPases to certain intracellular signaling pathways. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212744 Cd Length: 50 Bit Score: 36.27 E-value: 5.99e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146 1076 VIAMYDYKAANKDEMSFQKGQLITVLNKDNPDWWKGEVAGVTGLFPTNY 1124
Cdd:cd11810     2 VRALCHHVATDSGQLSFRKGDILRVIARVDDDWLLCTRGSTKGLVPLSY 50

Src Homology 3 domain of Amphiphysin and related domains; Amphiphysins function primarily in endocytosis and other membrane remodeling events. They exist in several isoforms and mammals possess two amphiphysin proteins from distinct genes. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin, and synaptojanin. They function in synaptic vesicle endocytosis. Human autoantibodies to amphiphysin I hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy. Amphiphysins contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. The SH3 domain of amphiphysins bind proline-rich motifs present in binding partners such as dynamin, synaptojanin, and nsP3. It also belongs to a subset of SH3 domains that bind ubiquitin in a site that overlaps with the peptide binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212724 [Multi-domain] Cd Length: 64 Bit Score: 36.92 E-value: 6.20e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEGE------WWRGCIGDQT--GLFPSNYVKP 984
Cdd:cd11790     7 ATHDYTAEDTDELTFEKGDVILVIPFDDPeeqdegWLMGVKESTGcrGVFPENFTER 63

Second Src Homology 3 domain of SH3 domain containing ring finger proteins; This model represents the second SH3 domain of SH3RF1 (or POSH), SH3RF2 (or POSHER), SH3RF3 (POSH2), and similar domains. Members of this family are scaffold proteins that function as E3 ubiquitin-protein ligases. They all contain an N-terminal RING finger domain and multiple SH3 domains; SH3RF1 and SH3RF3 have four SH3 domains while SH3RF2 has three. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3RF2 acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212721 [Multi-domain] Cd Length: 53 Bit Score: 36.54 E-value: 6.26e-03

                          10        20        30
                  ....*....|....*....|....*....|....
gi 688602146  869 LGFCKDDIITVLEK-QENWWYGELKEKRGWFPCS 901
Cdd:cd11787    19 LTFKKGDVITVIRRvDENWAEGRLGDKIGIFPIS 52

Src homology 3 domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; PSTPIP1, also called CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212758 [Multi-domain] Cd Length: 53 Bit Score: 36.58 E-value: 6.34e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 688602146  752 YRALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11824     2 YSVLYDYTAQEDDELSISKGDVVAVIEKG--EDGWWTVERNGQKGLVPGTYLE 52

Src Homology 3 domain of Membrane Protein, Palmitoylated 5 (or MAGUK p55 subfamily member 5); MPP5, also called PALS1 (Protein associated with Lin7) or Nagie oko protein in zebrafish or Stardust in Drosophila, is a scaffolding protein which associates with Crumbs homolog 1 (CRB1), CRB2, or CRB3 through its PDZ domain and with PALS1-associated tight junction protein (PATJ) or multi-PDZ domain protein 1 (MUPP1) through its L27 domain. The resulting tri-protein complexes are core proteins of the Crumb complex, which localizes at tight junctions or subapical regions, and is involved in the maintenance of apical-basal polarity in epithelial cells and the morphogenesis and function of photoreceptor cells. MPP5 is critical for the proper stratification of the retina and is also expressed in T lymphocytes where it is important for TCR-mediated activation of NFkB. Drosophila Stardust exists in several isoforms, some of which show opposing functions in photoreceptor cells, which suggests that the relative ratio of different Crumbs complexes regulates photoreceptor homeostasis. MPP5 contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212969 Cd Length: 63 Bit Score: 36.62 E-value: 6.34e-03

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 688602146 1090 MSFQKGQLITVLNKDNPDWWKGEVAG------VTGLFPT 1122
Cdd:cd12036    23 LSFQKGDILHVISQEDPNWWQAYREGeednqsLAGLIPS 61

Second Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212835 [Multi-domain] Cd Length: 55 Bit Score: 36.52 E-value: 6.55e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHV 903
Cdd:cd11902     3 AFVKFAYVAEREDELSLVKGSRVTVMEKcSDGWWRGSYNGQIGWFPSNYV 52

PH domain; PH stands for pleckstrin homology.

Pssm-ID: 459697 [Multi-domain] Cd Length: 105 Bit Score: 37.93 E-value: 6.84e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146  1379 LLHSGKLHKTKSS-----KELWALLFNDFLLLtYTSKQFSSSPDklfnpnsntqykmYKTPVFLNEVLVKMPSDPSSDDP 1453
Cdd:pfam00169    1 VVKEGWLLKKGGGkkkswKKRYFVLFDGSLLY-YKDDKSGKSKE-------------PKGSISLSGCEVVEVVASDSPKR 66

                           90       100       110
                   ....*....|....*....|....*....|....*...
gi 688602146  1454 --VFHISHID----RVYTLKTDTINERTTWVQKIKAAS 1485
Cdd:pfam00169   67 kfCFELRTGErtgkRTYLLQAESEEERKDWIKAIQSAI 104

rad50; All proteins in this family for which functions are known are involvedin recombination, recombinational repair, and/or non-homologous end joining.They are components of an exonuclease complex with MRE11 homologs. This family is distantly related to the SbcC family of bacterial proteins.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University).

Pssm-ID: 129694 [Multi-domain] Cd Length: 1311 Bit Score: 41.19 E-value: 6.90e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   452 SKRVELQTQKEKEQNDIQRlkdrkrsLEIELEAVGNKHKQISSQLRDAKSKRQGQWAELELINQRRD---VCITD---IN 525
Cdd:TIGR00606  723 KRRDEMLGLAPGRQSIIDL-------KEKEIPELRNKLQKVNRDIQRLKNDIEEQETLLGTIMPEEEsakVCLTDvtiME 795

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   526 SLQLQFDEMQRQLNQLGPEKQRlADRLVHFTQnissplindVKQSVCEKDRSCRKLKEQLDVLERETTAKLSQMEQYNKE 605
Cdd:TIGR00606  796 RFQMELKDVERKIAQQAAKLQG-SDLDRTVQQ---------VNQEKQEKQHELDTVVSKIELNRKLIQDQQEQIQHLKSK 865

                          170       180       190
                   ....*....|....*....|....*....|...
gi 688602146   606 IKELRQKQSQQQDVLE---QLRRVRSDKLKELQ 635
Cdd:TIGR00606  866 TNELKSEKLQIGTNLQrrqQFEEQLVELSTEVQ 898

Second Src Homology 3 domain of SH3 domain containing ring finger protein 1, an E3 ubiquitin-protein ligase; SH3RF1 is also called POSH (Plenty of SH3s) or SH3MD2 (SH3 multiple domains protein 2). It is a scaffold protein that acts as an E3 ubiquitin-protein ligase. It plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. It contains an N-terminal RING finger domain and four SH3 domains. This model represents the second SH3 domain, located C-terminal of the first SH3 domain at the N-terminal half, of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212863 Cd Length: 55 Bit Score: 36.51 E-value: 7.15e-03

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 688602146  869 LGFCKDDIITVLEK-QENWWYGELKEKRGWFPCSHV 903
Cdd:cd11930    20 LPFAKDDILTVIRRvDENWAEGMLGDKIGIFPISYV 55

Third Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the third SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212950 Cd Length: 53 Bit Score: 36.28 E-value: 7.30e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLEKQEN-WWYGELKEKRGWFPCSHV 903
Cdd:cd12017     3 FTIGEFQATIQDGISFQKGQKVEVIDKNPSgWWYVKIDGKEGWAPSSYI 51

Src Homology 3 domain of Membrane Protein, Palmitoylated 6 (or MAGUK p55 subfamily member 6); MPP6, also called Veli-associated MAGUK 1 (VAM-1) or PALS2, is a scaffolding protein that binds to Veli-1, a homolog of Caenorhabditis Lin-7. It is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212971 Cd Length: 61 Bit Score: 36.58 E-value: 7.33e-03

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 688602146 1090 MSFQKGQLITVLNKDNPDWWKG---EVAGVTGLFPTNYV 1125
Cdd:cd12038    23 LKFSKGEILQIVNREDPNWWQAshvKEGGSAGLIPSQFL 61

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member 4; CASS4, also called HEPL (HEF1-EFS-p130Cas-like), localizes to focal adhesions and plays a role in regulating FAK activity, focal adhesion integrity, and cell spreading. It is most abundant in blood cells and lung tissue, and is also found in high levels in leukemia and ovarian cell lines. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212933 Cd Length: 57 Bit Score: 36.40 E-value: 7.37e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  855 AVALCEWSAKTDSHLGFCKDDIITVLEKQ----ENWWYGELKEKRGWFPCSHVSV 905
Cdd:cd12000     3 ARALYDNKADCSDELAFRRGDILTVLEQNvpgsEGWWKCLLHGRQGLAPANRLQL 57

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212754 [Multi-domain] Cd Length: 54 Bit Score: 36.29 E-value: 7.57e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 688602146  753 RALYPFTARNSDELTLEADCFIQV-DEStvrETGWLYGSYSGNRGWFPESYAER 805
Cdd:cd11820     4 RALYDFEAAEDNELTFKAGEIITVlDDS---DPNWWKGSNHRGEGLFPANFVTA 54

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor; ASEF, also called ARHGEF4, exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli). GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF can activate Rac1 or Cdc42. Truncated ASEF, which is found in colorectal cancers, is constitutively active and has been shown to promote angiogenesis and cancer cell migration. ASEF contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212906 [Multi-domain] Cd Length: 73 Bit Score: 36.92 E-value: 8.18e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 688602146  936 ALYTYESPESGDLTFSAEDVVLVTEKEG-EWWRGCIGDQTGLFPSNYVK 983
Cdd:cd11973    22 ALWDHVTMDDQELGFKAGDVIEVMDATNkEWWWGRVLDSEGWFPASFVR 70

Src homology 3 domain of JNK-interacting proteins 1 and 2, and similar domains; JNK-interacting proteins (JIPs) function as scaffolding proteins for c-Jun N-terminal kinase (JNK) signaling pathways. They bind to components of Mitogen-activated protein kinase (MAPK) pathways such as JNK, MKK, and several MAP3Ks such as MLK and DLK. There are four JIPs (JIP1-4); all contain a JNK binding domain. JIP1 and JIP2 also contain SH3 and Phosphotyrosine-binding (PTB) domains. Both are highly expressed in the brain and pancreatic beta-cells. JIP1 functions as an adaptor linking motor to cargo during axonal transport and also is involved in regulating insulin secretion. JIP2 form complexes with fibroblast growth factor homologous factors (FHFs), which facilitates activation of the p38delta MAPK. The SH3 domain of JIP1 homodimerizes at the interface usually involved in proline-rich ligand recognition, despite the lack of this motif in the domain itself. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212735 Cd Length: 55 Bit Score: 36.13 E-value: 9.00e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  751 TYRALYPFTARNSDELTLEADCFIQVDESTvrETGWLYGS--YSGNRGWFPESYA 803
Cdd:cd11801     1 THRALHKFIPRHEDEIELDIGDPVYVEQEA--DDLWCEGTnlRTGQRGIFPAAYV 53

Src homology 3 domain of Src kinase-like Protein Tyrosine Kinases; Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, Yes, and Brk. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Src kinases are overexpressed in a variety of human cancers, making them attractive targets for therapy. They are also implicated in acute inflammatory responses and osteoclast function. Src, Fyn, Yes, and Yrk are widely expressed, while Blk, Lck, Hck, Fgr, Lyn, and Brk show a limited expression pattern. This subfamily also includes Drosophila Src42A, Src oncogene at 42A (also known as Dsrc41) which accumulates at sites of cell-cell or cell-matrix adhesion, and participates in Drosphila development and wound healing. It has been shown to promote tube elongation in the tracheal system, is essential for proper cell-cell matching during dorsal closure, and regulates cell-cell contacts in developing Drosophila eyes. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212779 [Multi-domain] Cd Length: 52 Bit Score: 36.02 E-value: 9.01e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 688602146  856 VALCEWSAKTDSHLGFCKDDIITVLEK-QENWWYGELKE--KRGWFP 899
Cdd:cd11845     3 VALYDYEARTDDDLSFKKGDRLQILDDsDGDWWLARHLStgKEGYIP 49

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

Pssm-ID: 274008 [Multi-domain] Cd Length: 1179 Bit Score: 40.81 E-value: 9.43e-03

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   451 KSKRVELQTQKEKEQNDIQRLKD-------RKRSLEIELEAVgNKHKQISSQLRDAkskrqgqwaELELINQRRDVCITD 523
Cdd:TIGR02168  171 KERRKETERKLERTRENLDRLEDilnelerQLKSLERQAEKA-ERYKELKAELREL---------ELALLVLRLEELREE 240

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   524 INSLQLQFDEMQRQLNQLGPEKQRLADRLVhftqnissplindvkqsvcEKDRSCRKLKEQLDVLERE---TTAKLSQME 600
Cdd:TIGR02168  241 LEELQEELKEAEEELEELTAELQELEEKLE-------------------ELRLEVSELEEEIEELQKElyaLANEISRLE 301

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688602146   601 QynkEIKELRQKQSQQQDVLEQLrrvrSDKLKELQRHRKEEEERKRKKEEEAARQAQLEQERLEQEEAErqRKLAQEREA 680
Cdd:TIGR02168  302 Q---QKQILRERLANLERQLEEL----EAQLEELESKLDELAEELAELEEKLEELKEELESLEAELEEL--EAELEELES 372

                          250       260
                   ....*....|....*....|....*
gi 688602146   681 KLRE-----EQQRQALARLLEAQEQ 700
Cdd:TIGR02168  373 RLEEleeqlETLRSKVAQLELQIAS 397

Src homology 3 domain of Cortactin; Cortactin was originally identified as a substrate of Src kinase. It is an actin regulatory protein that binds to the Arp2/3 complex and stabilizes branched actin filaments. It is involved in cellular processes that affect cell motility, adhesion, migration, endocytosis, and invasion. It is expressed ubiquitously except in hematopoietic cells, where the homolog hematopoietic lineage cell-specific 1 (HS1) is expressed instead. Cortactin contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region interacts with the Arp2/3 complex and F-actin, and is crucial in regulating branched actin assembly. Cortactin also serves as a scaffold and provides a bridge to the actin cytoskeleton for membrane trafficking and signaling proteins that bind to its SH3 domain. Binding partners for the SH3 domain of cortactin include dynamin2, N-WASp, MIM, FGD1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212892 [Multi-domain] Cd Length: 53 Bit Score: 35.86 E-value: 9.76e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 688602146  754 ALYPFTARNSDELTLEADCFI----QVDEstvretGWLYGSYSGNRGWFPESYAE 804
Cdd:cd11959     4 ALYDYQAADDDEISFDPDDIItnieMIDE------GWWRGVCRGKYGLFPANYVE 52