Domain in Myosin and Kinesin Tails; Domain present twice in myosin-VIIa, and also present in 3 other myosins.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829   960 YTKAPIQESLLSLSDDV-SKLAVASFLALMRFMGDQSKPRGKDEMDLLYELLKLC-QQEKLRDEIYCQVIKQVTGHPRPE 1037
Cdd:smart00139    1 YTKDPIKTSLLKLESDElQKEAVKIFKAILKFMGDIPLPRPDSHLDLVQFILQKGlDHPELRDEIYCQLIKQLTDNPSRQ 80

                            90       100       110       120       130       140
                    ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462557829  1038 HCTRGWSFLSLLTGFFPPSTRLMPYLTKFLQ---DSGPSQELARSSQEHLQRTVKYGGrRRMPP 1098
Cdd:smart00139   81 SEERGWQLLYLCTSLFPPSERLLPYLLQFLSrraDPGSEQGLAKYCLYRLERTLKNGA-RKQPP 143

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2462557829  802 YVIALRSYITDNCSLLSFHRGDLIKLLPVATLEPGWQFGSAGGRSGLFPADIVQP 856
Cdd:cd12068      1 YVVALRSYITDDKSLLSFHRGDLIKLLPMAGLEPGWQFGSTGGRSGLFPADIVQP 55

Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829  704 FSRFF---PVSGES--GSDVqLLAVSHRGLRLLKvtqgpglrpDQLKILCSYSFAEVLGVECR-----GGSTLELS-LKS 772
Cdd:cd13198      3 FSRFFeatKFSGPSlpKSEV-IIAVNWTGIYFVD---------EQEQVLLELSFPEITGVSSSrgkrdGGQSFTLTtIQG 72

                           90       100
                   ....*....|....*....|....*.
gi 2462557829  773 EQLVLHTARARAIEALVELFLNELKK 798
Cdd:cd13198     73 EEFVFQSPNAEDIAELVNYFLEGLRK 98

Domain in Myosin and Kinesin Tails; Domain present twice in myosin-VIIa, and also present in 3 other myosins.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829   960 YTKAPIQESLLSLSDDV-SKLAVASFLALMRFMGDQSKPRGKDEMDLLYELLKLC-QQEKLRDEIYCQVIKQVTGHPRPE 1037
Cdd:smart00139    1 YTKDPIKTSLLKLESDElQKEAVKIFKAILKFMGDIPLPRPDSHLDLVQFILQKGlDHPELRDEIYCQLIKQLTDNPSRQ 80

                            90       100       110       120       130       140
                    ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462557829  1038 HCTRGWSFLSLLTGFFPPSTRLMPYLTKFLQ---DSGPSQELARSSQEHLQRTVKYGGrRRMPP 1098
Cdd:smart00139   81 SEERGWQLLYLCTSLFPPSERLLPYLLQFLSrraDPGSEQGLAKYCLYRLERTLKNGA-RKQPP 143

FERM domain C-lobe of Myosin XV (MyoXV/Myo15); MyoXV, a MyTH-FERM myosin, are actin-based motor proteins essential for a variety of biological processes in actin cytoskeleton function. Specifically MyoXV functions in the actin organization in hair cells of the organ of Corti. Mutations in Human MyoXVa causes non-syndromic deafness, DFNB3 and the mouse shaker-2 mutation. MyoXV consists of a N-terminal motor/head region, a neck made of 1-3 IQ motifs, and a tail that consists of either a myosin tail homology 4 (MyTH4) domains, followed by an SH3 domain, and a MyTH-FERM domains as in rat Myo15 or two MyTH-FERM domains separated by a SH3 domain as in human Myo15A. The MyTH-FERM domains are thought to mediate dimerization and binding to other proteins or cargo. The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829 1306 GYTVYGVLRVSMQALSGPTLLGLNRQHLILMDPSSQSLYCRIALKSLQRLHLLSPlEEKGPPGLEVNYGSADNPQTIWFE 1385
Cdd:cd13201      1 GSNFFYVQRVSDPRLPGPCLLALNREGLHFLDPKTHETLLRIPLKEVQSTRKLRP-LEDGTPFLDIKYGNLMQQRTIRLE 79

                           90       100
                   ....*....|....*....|..
gi 2462557829 1386 LPQAQELLYTTVFLIDSSASCT 1407
Cdd:cd13201     80 TDQAHEISRLIAQYIEEASENR 101

FERM central domain; This domain is the central structural domain of the FERM domain.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829 1196 ETPLHFDNSTYISTHYSQVLWDYLQGKLPVSakaDAQLARLAALQHL-----SKANRNTPSGQDLLAYVPKQLQRQVNTA 1270
Cdd:pfam00373    1 DLELLLQDEVTRHLLYLQAKDDILEGRLPCS---EEEALLLAALQLQaefgdYQPSSHTSEYLSLESFLPKQLLRKMKSK 77

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|
gi 2462557829 1271 SIKNLMGQELRRLEGHSPQEAQISFIEAMSQLPLFGYTVY 1310
Cdd:pfam00373   78 ELEKRVLEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

FERM domain B-lobe; The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases, the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829 1210 HYSQVLWDYLQGKLPVSakaDAQLARLAALQHLSK-----ANRNTPSGQDLLAYVPKQLQRQVNTASIKNLMGQELRRLE 1284
Cdd:cd14473      5 LYLQVKRDILEGRLPCS---EETAALLAALALQAEygdydPSEHKPKYLSLKRFLPKQLLKQRKPEEWEKRIVELHKKLR 81

                           90
                   ....*....|....*...
gi 2462557829 1285 GHSPQEAQISFIEAMSQL 1302
Cdd:cd14473     82 GLSPAEAKLKYLKIARKL 99

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.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*...
gi 2462557829   799 DSGYVIALRSYITDNCSLLSFHRGDLIKLLpvATLEPGWQFG-SAGGRSGLFPADIVQ 855
Cdd:smart00326    1 EGPQVRALYDYTAQDPDELSFKKGDIITVL--EKSDDGWWKGrLGRGKEGLFPSNYVE 56

Domain in Myosin and Kinesin Tails; Domain present twice in myosin-VIIa, and also present in 3 other myosins.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829   960 YTKAPIQESLLSLSDDV-SKLAVASFLALMRFMGDQSKPRGKDEMDLLYELLKLC-QQEKLRDEIYCQVIKQVTGHPRPE 1037
Cdd:smart00139    1 YTKDPIKTSLLKLESDElQKEAVKIFKAILKFMGDIPLPRPDSHLDLVQFILQKGlDHPELRDEIYCQLIKQLTDNPSRQ 80

                            90       100       110       120       130       140
                    ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462557829  1038 HCTRGWSFLSLLTGFFPPSTRLMPYLTKFLQ---DSGPSQELARSSQEHLQRTVKYGGrRRMPP 1098
Cdd:smart00139   81 SEERGWQLLYLCTSLFPPSERLLPYLLQFLSrraDPGSEQGLAKYCLYRLERTLKNGA-RKQPP 143

FERM domain C-lobe of Myosin XV (MyoXV/Myo15); MyoXV, a MyTH-FERM myosin, are actin-based motor proteins essential for a variety of biological processes in actin cytoskeleton function. Specifically MyoXV functions in the actin organization in hair cells of the organ of Corti. Mutations in Human MyoXVa causes non-syndromic deafness, DFNB3 and the mouse shaker-2 mutation. MyoXV consists of a N-terminal motor/head region, a neck made of 1-3 IQ motifs, and a tail that consists of either a myosin tail homology 4 (MyTH4) domains, followed by an SH3 domain, and a MyTH-FERM domains as in rat Myo15 or two MyTH-FERM domains separated by a SH3 domain as in human Myo15A. The MyTH-FERM domains are thought to mediate dimerization and binding to other proteins or cargo. The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829 1306 GYTVYGVLRVSMQALSGPTLLGLNRQHLILMDPSSQSLYCRIALKSLQRLHLLSPlEEKGPPGLEVNYGSADNPQTIWFE 1385
Cdd:cd13201      1 GSNFFYVQRVSDPRLPGPCLLALNREGLHFLDPKTHETLLRIPLKEVQSTRKLRP-LEDGTPFLDIKYGNLMQQRTIRLE 79

                           90       100
                   ....*....|....*....|..
gi 2462557829 1386 LPQAQELLYTTVFLIDSSASCT 1407
Cdd:cd13201     80 TDQAHEISRLIAQYIEEASENR 101

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 2462557829  802 YVIALRSYITDNCSLLSFHRGDLIKLLPVAT-LEPGWQFGSAGGRSGLFPADIVQP 856
Cdd:cd11884      1 YVVAVRAYITRDQTLLSFHKGDVIKLLPKEGpLDPGWLFGTLDGRSGAFPKEYVQP 56

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829  1114 LLIHLPGGVDYRTNIQTFTVAAEVQEELCRQMGItepQEVQEFALFLIKEKSQLVRPLQPAEYLnsvvVDQDVSLHSRRL 1193
Cdd:smart00295    2 LKVYLLDGTTLEFEVDSSTTAEELLETVCRKLGI---RESEYFGLQFEDPDEDLRHWLDPAKTL----LDQDVKSEPLTL 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829  1194 H------WETPLHF--DNSTYIStHYSQVLWDYLQGKLPVSakaDAQLARLAALQHLSKANRNTPSGQDLL------AYV 1259
Cdd:smart00295   75 YfrvkfyPPDPNQLkeDPTRLNL-LYLQVRNDILEGRLPCP---EEEALLLAALALQAEFGDYDEELHDLRgelslkRFL 150

                           170       180       190       200       210
                    ....*....|....*....|....*....|....*....|....*....|.
gi 2462557829  1260 PKQLQRQVNTASIKNLMGQELRRLEGHSPQEAQISFIEAMSQLPLFGYTVY 1310
Cdd:smart00295  151 PKQLLDSRKLKEWRERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

Src Homology 3 domain of 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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462557829  802 YVIALRSYITDNCSLLSFHRGDLIKLLP-----------------VATLEP--------GWQFGSAGGRSGLFPADIVQP 856
Cdd:cd12067      1 YVVAVRNYLPEDPALLSFHKGDIIHLQPlegpkvgqyygcvvrkkVMYLEElkrgtpdfGWKFGAIHGRSGVFPAELVQP 80

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 2462557829  802 YVIALRSYITDNCSLLSFHRGDLIKLLpvATLEPGWQFG-SAGGRSGLFPA 851
Cdd:cd00174      1 YARALYDYEAQDDDELSFKKGDIITVL--EKDDDGWWEGeLNGGREGLFPA 49

Variant SH3 domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 2462557829  805 ALRSYITDNCSLLSFHRGDLIKLLPVAtlEPGWQFGSAGGRSGLFPADIVQ 855
Cdd:pfam14604    1 ALYPYEPKDDDELSLQRGDVITVIEES--EDGWWEGINTGRTGLVPANYVE 49

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2462557829  802 YVIALRSYITDNCSLLSFHRGDLIKLLPVAtlEPGWQFGSAGGRSGLFPADIVQP 856
Cdd:cd11951      1 FVQAQYDFSAEDPSQLSFRRGDIIEVLDCP--DPNWWRGRISGRVGFFPRNYVHP 53

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 2462557829  805 ALRSYITDNCSLLSFHRGDLIKLLpvATLEPGWQFGSAGGRSGLFPADIVQ 855
Cdd:cd11786      4 ALYNYEGKEPGDLSFKKGDIILLR--KRIDENWYHGECNGKQGFFPASYVQ 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 2462557829  802 YVIALRSYITDNCSLLSFHRGDLIKLLPVATLEPGWQFGSAGGRSGLFPADIV 854
Cdd:cd12056      3 YCKALFHYEGTNEDELDFKEGEIILIISKDTGEPGWWKGELNGKEGVFPDNFV 55

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2462557829  802 YVIALRSYITDNCSLLSFHRGDLIKLLPVATLEPGWQFGSAGGRSGLFPADIVQP 856
Cdd:cd11875      1 KARVLFDYEAENEDELTLREGDIVTILSKDCEDKGWWKGELNGKRGVFPDNFVEP 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2462557829  801 GYVIALRSYITDNCSLLSFHRGDLIKLLPVAtlEPGWQFGSAGGRSGLFPADIVQ 855
Cdd:cd11996      1 CQVIAMYDYTANNEDELSFSKGQLINVLNKD--DPDWWQGEINGVTGLFPSNYVK 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 2462557829  803 VIALRSYITDNCSLLSFHRGDLIKLLpVATLEPGWQFGSAGGRSGLFPADIVQP 856
Cdd:cd11882      2 ARALYACKAEDESELSFEPGQIITNV-QPSDEPGWLEGTLNGRTGLIPENYVEF 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.

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gi 2462557829  802 YVIALRSYITDNCSLLSFHRGDLIKllpVATLEPGWQFGSAGGRSGLFPADIVQP 856
Cdd:cd11838      1 EYIALYPYESNEPGDLTFNAGDVIL---VTKKDGEWWTGTIGDRTGIFPSNYVRP 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.

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gi 2462557829  803 VIALRSYITDNCSLLSFHRGDLIKLLpVATLEPGWQFGS--AGGRSGLFPADIVQP 856
Cdd:cd11779      3 VKALYPHAAGGETQLSFEEGDVITLL-GPEPRDGWHYGEneRSGRRGWFPIAYTEP 57

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.

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gi 2462557829  802 YVIALRSYITDNCSLLSFHRGDLIKLLpvATLEPGWQFGSAGGRSGLFPADIVQ 855
Cdd:cd11826      1 KVVALYDYTADKDDELSFQEGDIIYVT--KKNDDGWYEGVLNGVTGLFPGNYVE 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.

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gi 2462557829  803 VIALRSYITDNCSLLSFHRGDLIKLLpvATLEPGWQFGS-AGGRSGLFPADIV 854
Cdd:cd11812      2 VVALYDYTANRSDELTIHRGDIIRVL--YKDNDNWWFGSlVNGQQGYFPANYV 52

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.

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gi 2462557829  809 YITDNCSLLSFHRGDLIKLLPVATLEPGWQFGSAGGRSGLFPADIVQP 856
Cdd:cd12142      8 YNPVAPDELALKKGDVIEVISKETEDEGWWEGELNGRRGFFPDNFVMP 55

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.

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gi 2462557829  805 ALRSYITDNCSLLSFHRGDLIKLLpvatLE--PGWQFGSAGGRSGLFPADIVQ 855
Cdd:cd11827      4 ALYAYDAQDTDELSFNEGDIIEIL----KEdpSGWWTGRLRGKEGLFPGNYVE 52

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.

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gi 2462557829  817 LSFHRGDLIKLlpVATLEPGWQFGSAGGRSGLFPADIVQP 856
Cdd:cd11949     16 LGFRRGDFIEV--MDNSDPNWWKGACHGQTGMFPRNYVTP 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.

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gi 2462557829  802 YVIALRSYITDNCSLLSFHRGDLIKLLPVAtlEPGWQFGSAGGRSGLFPADIVQ 855
Cdd:cd11828      1 LAEALWDHVTMDPEELGFKAGDVIEVLDMS--DKDWWWGSIRDEEGWFPASFVR 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.

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gi 2462557829  805 ALRSYITDNCSLLSFHRGDLIKLLPVATLEPGWQFGSAGGRSGLFPADIVQ 855
Cdd:cd11988      6 ALYPFEARNHDEMSFNAGDIIQVDEKTVGEPGWLYGSFQGNFGWFPCNYVE 56

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.

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gi 2462557829  817 LSFHRGDLIKLlpVATLEPGWQFGSAGGRSGLFPADIVQ 855
Cdd:cd11803     17 LGFKEGDIITL--TNQIDENWYEGMVNGQSGFFPVNYVE 53