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 1972310391  486 FSEKPISQSLLADLGNEESKYAVETFHAIMKFMGDEPLKKSESMTDVVFKVLLICHRQPTLRDEVYCQLIKQTTSNISQk 565
Cdd:smart00139   1 YTKDPIKTSLLKLESDELQKEAVKIFKAILKFMGDIPLPRPDSHLDLVQFILQKGLDHPELRDEIYCQLIKQLTDNPSR- 79

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1972310391  566 pNSALRAWRLLTIITAYFPSSLTLKPYVLQYLGDNADEWQrpFHGTARICQTNMIQTFKYGGRKVLLNALEVQQIT 641
Cdd:smart00139  80 -QSEERGWQLLYLCTSLFPPSERLLPYLLQFLSRRADPGS--EQGLAKYCLYRLERTLKNGARKQPPSRLELEAIL 152

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 1972310391 360 FVRALEDYVTSEVNHLSFKQGDVIELLQEpegETPPVGNWLYGKIENRFGFLLAQYV 416
Cdd:cd11884     1 YVVAVRAYITRDQTLLSFHKGDVIKLLPK---EGPLDPGWLFGTLDGRSGAFPKEYV 54

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 1972310391  486 FSEKPISQSLLADLGNEESKYAVETFHAIMKFMGDEPLKKSESMTDVVFKVLLICHRQPTLRDEVYCQLIKQTTSNISQk 565
Cdd:smart00139   1 YTKDPIKTSLLKLESDELQKEAVKIFKAILKFMGDIPLPRPDSHLDLVQFILQKGLDHPELRDEIYCQLIKQLTDNPSR- 79

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1972310391  566 pNSALRAWRLLTIITAYFPSSLTLKPYVLQYLGDNADEWQrpFHGTARICQTNMIQTFKYGGRKVLLNALEVQQIT 641
Cdd:smart00139  80 -QSEERGWQLLYLCTSLFPPSERLLPYLLQFLSRRADPGS--EQGLAKYCLYRLERTLKNGARKQPPSRLELEAIL 152

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 1972310391  648 RQAFYISKDHNVSQTLRPITVAEEMIQELCNLLNVRslhEQQEFSLCYTVGKDKHLNYCKNDNYLMDIITESEhkklPFQ 727
Cdd:smart00295   1 VLKVYLLDGTTLEFEVDSSTTAEELLETVCRKLGIR---ESEYFGLQFEDPDEDLRHWLDPAKTLLDQDVKSE----PLT 73

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1972310391  728 FYLKRTVWVHP---LRYDNAAYIdSMFDQVIDDYLRGSLIstnslgqltaATTEEIIKLAAYLF-LLLPDNPKGL----N 799
Cdd:smart00295  74 LYFRVKFYPPDpnqLKEDPTRLN-LLYLQVRNDILEGRLP----------CPEEEALLLAALALqAEFGDYDEELhdlrG 142

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1972310391  800 AKTLPQIVPKSVIepKHRHQEEMVTRISRQLKMFGGrMRPAEAKSHFLELLSTWPTFGVLHY 861
Cdd:smart00295 143 ELSLKRFLPKQLL--DSRKLKEWRERIVELHKELIG-LSPEEAKLKYLELARKLPTYGVELF 201

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        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1972310391  357 KRKFVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIEN-RFGFLLAQYV 416
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSD------DGWWKGRLGRgKEGLFPSNYV 55

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 1972310391 750 MFDQVIDDYLRGSListnslgqltAATTEEIIKLAAYLFL-LLPDNPKGLNAKT---LPQIVPKSVIepKHRHQEEMVTR 825
Cdd:cd14473     5 LYLQVKRDILEGRL----------PCSEETAALLAALALQaEYGDYDPSEHKPKylsLKRFLPKQLL--KQRKPEEWEKR 72

                          90       100
                  ....*....|....*....|....*...
gi 1972310391 826 ISRQLKMFGGrMRPAEAKSHFLELLSTW 853
Cdd:cd14473    73 IVELHKKLRG-LSPAEAKLKYLKIARKL 99

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        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1972310391 362 RALEDYVTSEVNHLSFKQGDVIELLQEPEGEtppvgnWLYGK-IENRFGF 410
Cdd:pfam00018   1 VALYDYTAQEPDELSFKKGDIIIVLEKSEDG------WWKGRnKGGKEGL 44

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 1972310391  486 FSEKPISQSLLADLGNEESKYAVETFHAIMKFMGDEPLKKSESMTDVVFKVLLICHRQPTLRDEVYCQLIKQTTSNISQk 565
Cdd:smart00139   1 YTKDPIKTSLLKLESDELQKEAVKIFKAILKFMGDIPLPRPDSHLDLVQFILQKGLDHPELRDEIYCQLIKQLTDNPSR- 79

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1972310391  566 pNSALRAWRLLTIITAYFPSSLTLKPYVLQYLGDNADEWQrpFHGTARICQTNMIQTFKYGGRKVLLNALEVQQIT 641
Cdd:smart00139  80 -QSEERGWQLLYLCTSLFPPSERLLPYLLQFLSRRADPGS--EQGLAKYCLYRLERTLKNGARKQPPSRLELEAIL 152

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 1972310391  648 RQAFYISKDHNVSQTLRPITVAEEMIQELCNLLNVRslhEQQEFSLCYTVGKDKHLNYCKNDNYLMDIITESEhkklPFQ 727
Cdd:smart00295   1 VLKVYLLDGTTLEFEVDSSTTAEELLETVCRKLGIR---ESEYFGLQFEDPDEDLRHWLDPAKTLLDQDVKSE----PLT 73

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1972310391  728 FYLKRTVWVHP---LRYDNAAYIdSMFDQVIDDYLRGSLIstnslgqltaATTEEIIKLAAYLF-LLLPDNPKGL----N 799
Cdd:smart00295  74 LYFRVKFYPPDpnqLKEDPTRLN-LLYLQVRNDILEGRLP----------CPEEEALLLAALALqAEFGDYDEELhdlrG 142

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1972310391  800 AKTLPQIVPKSVIepKHRHQEEMVTRISRQLKMFGGrMRPAEAKSHFLELLSTWPTFGVLHY 861
Cdd:smart00295 143 ELSLKRFLPKQLL--DSRKLKEWRERIVELHKELIG-LSPEEAKLKYLELARKLPTYGVELF 201

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        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1972310391  357 KRKFVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIEN-RFGFLLAQYV 416
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSD------DGWWKGRLGRgKEGLFPSNYV 55

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 1972310391 360 FVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIENRFGFLLAQYV 416
Cdd:cd11805     1 RVQALYDFNPQEPGELEFRRGDIITVLDSSD------PDWWKGELRGRVGIFPANYV 51

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 1972310391 750 MFDQVIDDYLRGSListnslgqltAATTEEIIKLAAYLFL-LLPDNPKGLNAKT---LPQIVPKSVIepKHRHQEEMVTR 825
Cdd:cd14473     5 LYLQVKRDILEGRL----------PCSEETAALLAALALQaEYGDYDPSEHKPKylsLKRFLPKQLL--KQRKPEEWEKR 72

                          90       100
                  ....*....|....*....|....*...
gi 1972310391 826 ISRQLKMFGGrMRPAEAKSHFLELLSTW 853
Cdd:cd14473    73 IVELHKKLRG-LSPAEAKLKYLKIARKL 99

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1972310391 875 EVILTINKSGIQLLQPKSKEVFKERNYDQIVSVESIRKTAYKIVRLVI---NTMQgEETLDIKTDEADEISHLIGQYM 949
Cdd:cd13201    18 PCLLALNREGLHFLDPKTHETLLRIPLKEVQSTRKLRPLEDGTPFLDIkygNLMQ-QRTIRLETDQAHEISRLIAQYI 94

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 1972310391 360 FVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetPpvgNWLYGKIENRFGFLLAQYV 416
Cdd:cd11951     1 FVQAQYDFSAEDPSQLSFRRGDIIEVLDCPD---P---NWWRGRISGRVGFFPRNYV 51

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972310391 361 VRALEDYVTSEVNHLSFKQGDVIELLQePEgetpPVGNWLYGKIE--NRFGFLLAQYV 416
Cdd:cd11779     3 VKALYPHAAGGETQLSFEEGDVITLLG-PE----PRDGWHYGENErsGRRGWFPIAYT 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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972310391 361 VRALEDYVTSEVNHLSFKQGDVIELLQE-PEGetppvgnWLYGKIENRFGFLLAQYVD 417
Cdd:cd11827     2 CKALYAYDAQDTDELSFNEGDIIEILKEdPSG-------WWTGRLRGKEGLFPGNYVE 52

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.

                          10        20
                  ....*....|....*....|....*..
gi 1972310391 360 FVRALEDYVTSEVNHLSFKQGDVIELL 386
Cdd:cd11883     1 VVVALYDFTPKSKNQLSFKAGDIIYVL 27

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1972310391 363 ALEDYVTSEVNHLSFKQGDVIELLQEPEGETPPVGnWLYGKIENRFGFLLAQYV 416
Cdd:cd12058     4 ALYDYEASGEDELSLRRGDVVEVLSQDAAVSGDDG-WWAGKIRHRLGIFPANYV 56

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972310391 361 VRALEDYVTSEVNHLSFKQGDVIELLQEPEGETppvgNWLYGKIENRFGFLLAQYVD 417
Cdd:cd11842     2 AVALYDFAGEQPGDLAFQKGDIITILKKSDSQN----DWWTGRIGGREGIFPANYVE 54

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972310391 360 FVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIENRFGFLLAQYV 416
Cdd:pfam07653   1 YGRVIFDYVGTDKNGLTLKKGDVVKVLGKDN------DGWWEGETGGRVGLVPSTAV 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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1972310391 361 VRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIENRFGFLLAQYV 416
Cdd:cd11877     2 VRAKFNFEGTNEDELSFDKGDIITVTQVVE------GGWWEGTLNGKTGWFPSNYV 51

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.

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gi 1972310391 363 ALEDYVTSEVNHLSFKQGDVIELLQEPEGetppvgNWLYGKIENRFGFLLAQYV 416
Cdd:cd11833     4 ALYKFKPQENEDLEMRPGDKITLLDDSNE------DWWKGKIEDRVGFFPANFV 51

FERM domain C-lobe, repeat 1, of Myosin-like proteins; These myosin-like proteins are unidentified though they are sequence similar to myosin 1/myo1, myosin 7/myoVII, and myosin 10/myoX. These myosin-like proteins contain an N-terminal motor/head region and a C-terminal tail consisting of two myosin tail homology 4 (MyTH4) and twos FERM domains. In myoX the FERM domain forms a supramodule with its MyTH4 domain which binds to the negatively charged E-hook region in the tails of alpha- and beta-tubulin forming a proposed motorized link between actin filaments and microtubules and a similar thing might happen in these myosins. 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 first FERM_N repeat is present in this hierarchy. 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.

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gi 1972310391 876 VILTINKSGIQLLQPKSKEVFKERNYDQIVSVEsirktaykivrlvINTMQGEETLDIKTDEADEISHligqYMFVTGGA 955
Cdd:cd13203    19 LILGVHCDGFKFVNPDTKEILAEYRYSDLESIL-------------VNPSDDVLTLNLSKSVPDEHKC----FMFETPQK 81

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gi 1972310391 956 EERGS 960
Cdd:cd13203    82 EEIAS 86

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 1972310391 360 FVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIENRFGFLLAQYV 416
Cdd:cd11949     1 YVQALFDFDPQEDGELGFRRGDFIEVMDNSD------PNWWKGACHGQTGMFPRNYV 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.

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gi 1972310391 360 FVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIENRFGFLLAQYV 416
Cdd:cd11772     1 VFRALYDYEAQHPDELSFEEGDLLYISDKSD------PNWWKATCGGKTGLIPSNYV 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.

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gi 1972310391 361 VRALEDYVTSEVNHLSFKQGDVIELLQE-PEGetppvgnWLYGKIEN--RFGFLLAQYV 416
Cdd:cd11789     2 YRAMYDYAAADDDEVSFQEGDVIINVEIiDDG-------WMEGTVQRtgQSGMLPANYV 53

Src homology 3 domain of Sam And SH3 Domain Containing Protein 3; SASH3, also called SLY/SLY1 (SH3-domain containing protein expressed in lymphocytes), is expressed exclusively in lymhocytes and is essential in the full activation of adaptive immunity. It is involved in the signaling of T cell receptors. It was the first described member of the SLY family of proteins, which are adaptor proteins containing a central conserved region with a bipartite nuclear localization signal (NLS) as well as SAM (sterile alpha motif) 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 1972310391 362 RALEDYVTS--EVNHLSFKQGDVIELLqepegETPPVGNWLyGKIENRFGFLLAQYVD 417
Cdd:cd11968     4 RVHTDFIPSpyDGDSLKLQKGDIIQII-----EKPPVGTWT-GLLNNKVGTFKFIYVD 55

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 1972310391 362 RALEDYVTSEVNHLSFKQGDVIELLQEPEGetppvgNWLYGKIENRFGFLLAQYVD 417
Cdd:cd11803     4 RALYDFEPENEGELGFKEGDIITLTNQIDE------NWYEGMVNGQSGFFPVNYVE 53