Ankyrin repeat [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568946065 626 LLLDAALTGELDVVQQAVKEMNDPSQPNEEGITALHNAICGANYPIVDFLIAAGANVNSPDSHGWTPLHCAASCNDTAIC 705
Cdd:COG0666   90 LLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEIV 169

                         90       100
                 ....*....|....*....|.
gi 568946065 706 TALVQHGAAIFATTlSDGATA 726
Cdd:COG0666  170 KLLLEAGADVNARD-NDGETP 189

Ankyrin repeat [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568946065 626 LLLDAALTGELDVVQQAVKEMNDPSQPNEEGITALHNAICGANYPIVDFLIAAGANVNSPDSHGWTPLHCAASCNDTAIC 705
Cdd:COG0666   90 LLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEIV 169

                         90       100
                 ....*....|....*....|.
gi 568946065 706 TALVQHGAAIFATTlSDGATA 726
Cdd:COG0666  170 KLLLEAGADVNARD-NDGETP 189

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 568946065   759 VYALWDYSAEFGDELSFREGESVTVLRRDGPeetDWWWASLH-GQEGYVPRNY 810
Cdd:smart00326   5 VRALYDYTAQDPDELSFKKGDIITVLEKSDD---GWWKGRLGrGKEGLFPSNY 54

ankyrin-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568946065 648 DPSQPNEEGITALHNA--ICGANYPIVDFLIAAGANVNSPDSHGWTPLHCAASCNDTAICTALVQHGAAIFATTlSDGAT 725
Cdd:PHA03095 214 DPAATDMLGNTPLHSMatGSSCKRSLVLPLLIAGISINARNRYGQTPLHYAAVFNNPRACRRLIALGADINAVS-SDGNT 292

                 ..
gi 568946065 726 AI 727
Cdd:PHA03095 293 PL 294

Ty transposon capsid protein; Ty are yeast transposons. A 5.7kb transcript codes for p3 a fusion protein of TYA and TYB. The TYA protein is analogous to the gag protein of retroviruses. TYA a is cleaved to form 46kd protein which can form mature virion like particles. This entry corresponds to the capsid protein from Ty1 and Ty2 transposons.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568946065   19 SLAMKHMDLKQMELDTAAAKVDELTKQLESLWSDSPAPPGAQAgVPSRMARYSTSPVPEHFGSRG--SPQKIATDGIEAR 96
Cdd:pfam01021   4 SVTSKEVHTNQDPLDVSASKLQEYDKDSTKANSQQTTTPGSSA-VPENHHHASPQPASVPPPQNGpySQQCMMTPNQANP 82

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 568946065   97 FGRSE-SAPSLHPYSP--LSPKGRPSSPRTPIYLQPDTYSSLDRAPSPRP 143
Cdd:pfam01021  83 SGWPFyGHPSMMPYTPyqMSPMYFPPGPQSQFPQYPSSVGTPLSTPSPES 132

Transient Receptor Potential channel, Vanilloid subfamily (TRPV), types 5 and 6; TRPV5 and TRPV6 (TRPV5/6) are two homologous members within the vanilloid subfamily of the transient receptor potential (TRP) family. TRPV5 and TRPV6 show only 30-40% homology with other members of the TRP family and have unique properties that differentiates them from other TRP channels. They mediate calcium uptake in epithelia and their expression is dramatically increased in numerous types of cancer. The structure of TRPV5/6 shows the typical topology features of all TRP family members, such as six transmembrane regions, a short hydrophobic stretch between transmembrane segments 5 and 6, which is predicted to form the Ca2+ pore, and large intracellular N- and C-terminal domains. The N-terminal domain of TRPV5/6 contains three ankyrin repeats. This structural element is present in several proteins and plays a role in protein-protein interactions. The N- and C-terminal tails of TRPV5/6 each contain an internal PDZ motif which can function as part of a molecular scaffold via interaction with PDZ-domain containing proteins. A major difference between the properties of TRPV5 and TRPV6 is in their tissue distribution: TRPV5 is predominantly expressed in the distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, with limited expression in extrarenal tissues. In contrast, TRPV6 has a broader expression pattern such as expression in the intestine, kidney, placenta, epididymis, exocrine tissues, and a few other tissues.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568946065 630 AALTGELDVVQQAVKEmnDPSQPNE-------EGITALHNAICGANYPIVDFLIAAGANVNSPDS--------------H 688
Cdd:cd22192   58 AALYDNLEAAVVLMEA--APELVNEpmtsdlyQGETALHIAVVNQNLNLVRELIARGADVVSPRAtgtffrpgpknliyY 135

                         90       100
                 ....*....|....*....|....*....
gi 568946065 689 GWTPLHCAASCNDTAICTALVQHGAAIFA 717
Cdd:cd22192  136 GEHPLSFAACVGNEEIVRLLIEHGADIRA 164

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 568946065 757 GVVYALWDYSAEFGDELSFREGESVTVLRRDGPEETDWWWASLHGQEGYVPRNYFGL 813
Cdd:cd11807    1 GVVYALFDYEAENGDELSFREGDELTVLRKGDDDETEWWWARLNDKEGYVPRNLLGL 57

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 568946065 757 GVVYALWDYSAEFGDELSFREGESVTVLRRDGPEETDWWWASLHGQEGYVPRNYFGL 813
Cdd:cd11953    1 GVVYALWDYEGESDDELSFKEGDCMTILRREDEDETEWWWARLNDKEGYVPRNLLGL 57

Ankyrin repeat [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568946065 626 LLLDAALTGELDVVQQAVKEMNDPSQPNEEGITALHNAICGANYPIVDFLIAAGANVNSPDSHGWTPLHCAASCNDTAIC 705
Cdd:COG0666  123 PLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEIV 202

                         90       100
                 ....*....|....*....|..
gi 568946065 706 TALVQHGAAIFATTlSDGATAI 727
Cdd:COG0666  203 KLLLEAGADVNAKD-NDGKTAL 223

Ankyrin repeats (3 copies);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568946065  627 LLDAALTGELDVVQQAVKEMNDPSQPNEEGITALHNAICGANYPIVDFLIaAGANVNSPDsHGWTPLHCAASCNDTAICT 706
Cdd:pfam12796   1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLL-EHADVNLKD-NGRTALHYAARSGHLEIVK 78

                  ....*..
gi 568946065  707 ALVQHGA 713
Cdd:pfam12796  79 LLLEKGA 85

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 568946065 758 VVYALWDYSAEFGDELSFREGESVTVLRRDGPeetDWWWASLH-GQEGYVPRNY 810
Cdd:cd00174    1 YARALYDYEAQDDDELSFKKGDIITVLEKDDD---GWWEGELNgGREGLFPANY 51

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 568946065 758 VVYALWDYSAEFGDELSFREGESVTVLRR-DGPEETDWWWASLHGQEGYVPRNYFG 812
Cdd:cd11800    1 YYYALYTFEARSPGELSVTEGQVVTVLEKhDLKGNPEWWLVEDRGKQGYVPSNYLA 56

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 568946065 760 YALWDYSAEFGDELSFREGESVTVLRRDgpeETDWWWASLHGQEGYVPRNY 810
Cdd:cd11856    3 VAIADYEAQGDDEISLQEGEVVEVLEKN---DSGWWYVRKGDKEGWVPASY 50

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 568946065 761 ALWDYSAEFGDELSFREGESVTVLRRDGPEETDWWWASLHGQEGYVPRN 809
Cdd:cd11844    4 ALYDNVAESPDELAFRRGDILTVLEQNTAGLEGWWLCSLRGRQGIAPGN 52

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 568946065 761 ALWDYSAEFGDELSFREGESVTVLRRDGpeetDWWWASLHGQ------EGYVPRNY 810
Cdd:cd11847    4 ALWDFKARGDEELSFQAGDQFRIAERSG----DWWTALKLDRaggvvaQGFVPNNY 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 568946065 758 VVYALWDYSAEFGDELSFREGESVTVLRRDGPeetDWWWASLHGQEGYVPRNYF 811
Cdd:cd11772    1 VFRALYDYEAQHPDELSFEEGDLLYISDKSDP---NWWKATCGGKTGLIPSNYV 51

Variant SH3 domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 568946065  761 ALWDYSAEFGDELSFREGESVTVLRRDGPeetDWWWASLHGQEGYVPRNY 810
Cdd:pfam14604   1 ALYPYEPKDDDELSLQRGDVITVIEESED---GWWEGINTGRTGLVPANY 47

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 568946065 761 ALWDYSAEFGDELSFREGESVTVLRRDgpeeTDWWWASLHGQEGYVPRNY 810
Cdd:cd11947    4 GKFDFTASGEDELSFKKGDVLKILSSD----DIWFKAELNGEEGYVPKNF 49

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 568946065 756 NGVVYALWDYSAEFGDELSFREGESVTVLRRDGPEETDWWWASLHGQEGYVPRN 809
Cdd:cd12001    2 NVLAKALYDNVAESPDELSFRKGDIMTVLERDTQGLDGWWLCSLHGRQGIVPGN 55

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 568946065 758 VVYALWDYSAEFGDELSFREGESVTVLR-RDGPEETDWWWASLHGQEGYVPRNYFG 812
Cdd:cd12141    1 VYYAVYTFKARSPNELSVSANQRVRILEfSDLTGNKEWWLAEANGQKGYVPSNYIR 56

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 568946065 759 VYALWDYSAEFGDELSFREGESVTVLRRDGPeetDWWWASLHGQEGYVPRNY 810
Cdd:cd11805    2 VQALYDFNPQEPGELEFRRGDIITVLDSSDP---DWWKGELRGRVGIFPANY 50

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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 568946065  761 ALWDYSAEFGDELSFREGESVTVLRRdgpEETDWWWASLH-GQEGYVP 807
Cdd:pfam00018   2 ALYDYTAQEPDELSFKKGDIIIVLEK---SEDGWWKGRNKgGKEGLIP 46

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 568946065 759 VYALWDYSAEFGDELSFREGESVTVLRRDGPeetDWWWASLHGQEGYVPRNYFGL 813
Cdd:cd11995    3 VIGMYDYTAQNDDELAFSKGQIINVLNKEDP---DWWKGELNGQVGLFPSNYVKL 54

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.

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gi 568946065 761 ALWDYSAEFGDELSFREGESVTVLRRDGpEETDWWWASLHGQEGYVPRNY 810
Cdd:cd11875    4 VLFDYEAENEDELTLREGDIVTILSKDC-EDKGWWKGELNGKRGVFPDNF 52

ankyrin-like protein; Provisional

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gi 568946065 648 DPSQPNEEGITALHNA--ICGANYPIVDFLIAAGANVNSPDSHGWTPLHCAASCNDTAICTALVQHGAAIFATTlSDGAT 725
Cdd:PHA03095 214 DPAATDMLGNTPLHSMatGSSCKRSLVLPLLIAGISINARNRYGQTPLHYAAVFNNPRACRRLIALGADINAVS-SDGNT 292

                 ..
gi 568946065 726 AI 727
Cdd:PHA03095 293 PL 294

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.

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gi 568946065 761 ALWDYSAEFGDELSFREGESVTVLRRDgpEETDWWWASLHGQEGYVPRNYFGL 813
Cdd:cd11948    4 ALYSFQATESDELPFQKGDILKILNME--DDQNWYKAELQGREGYIPKNYIKV 54

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.

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gi 568946065 761 ALWDYSAEFGDELSFREGESVTVLRrdgpEETD--WWWASLHGQEGYVPRNY 810
Cdd:cd11946    5 AKYDFKATADDELSFKRGDILKVLN----EECDqnWYKAELNGKDGFIPKNY 52

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.

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gi 568946065 761 ALWDYSAEFGDELSFREGESVTVLRRdgpEETDWWWA-SL-HGQEGYVPRNY 810
Cdd:cd12006    5 ALYDYEARTEDDLSFHKGEKFQILNS---SEGDWWEArSLtTGETGYIPSNY 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.

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gi 568946065 761 ALWDYSAEFGDELSFREGESVTVLRRdgpEETDWWWASLHGQEGYVPRNY 810
Cdd:cd11817    4 ALYDFTGETEEDLSFQRGDRILVTEH---LDAEWSRGRLNGREGIFPRAF 50

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.

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gi 568946065 758 VVYALWDYSAEFGDELSFREGESVTVLRRDGpeetDWWWA-SL-HGQEGYVPRNY 810
Cdd:cd12009    1 CVIAQYDFVPSNERDLQLKKGEKLQVLKSDG----EWWLAkSLtTGKEGYIPSNY 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.

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gi 568946065 761 ALWDYSAEFGDELSFREGESVTVLRRDGPEEtDWWWASLHGQEGYVPRNY 810
Cdd:cd11842    4 ALYDFAGEQPGDLAFQKGDIITILKKSDSQN-DWWTGRIGGREGIFPANY 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.

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gi 568946065 758 VVYALWDYSAEFGDELSFREGESVTVLRR--DGpeetdWWWASLHGQEGYVPRNY 810
Cdd:cd11766    1 PAVVKFNYEAQREDELSLRKGDRVLVLEKssDG-----WWRGECNGQVGWFPSNY 50

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.

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gi 568946065 761 ALWDYSAEFGDELSFREGESVTVLRRDGPeetDWWWASLHGQEGYVPRNY 810
Cdd:cd11809    4 AQFDYTGRSERELSFKKGDSLTLYRQVSD---DWWRGQLNGQDGLVPHKY 50

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.

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gi 568946065  761 ALWDYSAEFGDELSFREGESVTVLRRDGPEetdWWWASLHGQEGYVPRNY 810
Cdd:pfam07653   4 VIFDYVGTDKNGLTLKKGDVVKVLGKDNDG---WWEGETGGRVGLVPSTA 50