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 392927376    523 FSEKPISQSLLADLGNEESKYAVETFHAIMKFMGDEPLKKSESMTDVVFKVLLICHRQPTLRDEVYCQLIKQTTSNISQk 602
Cdd:smart00139    1 YTKDPIKTSLLKLESDELQKEAVKIFKAILKFMGDIPLPRPDSHLDLVQFILQKGLDHPELRDEIYCQLIKQLTDNPSR- 79

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392927376    603 pNSALRAWRLLTIITAYFPSSLTLKPYVLQYLGDNADEWQrpFHGTARICQTNMIQTFKYGGRKVLLNALEVQQIT 678
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 392927376  397 FVRALEDYVTSEVNHLSFKQGDVIELLQEpegETPPVGNWLYGKIENRFGFLLAQYV 453
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 392927376    523 FSEKPISQSLLADLGNEESKYAVETFHAIMKFMGDEPLKKSESMTDVVFKVLLICHRQPTLRDEVYCQLIKQTTSNISQk 602
Cdd:smart00139    1 YTKDPIKTSLLKLESDELQKEAVKIFKAILKFMGDIPLPRPDSHLDLVQFILQKGLDHPELRDEIYCQLIKQLTDNPSR- 79

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392927376    603 pNSALRAWRLLTIITAYFPSSLTLKPYVLQYLGDNADEWQrpFHGTARICQTNMIQTFKYGGRKVLLNALEVQQIT 678
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 392927376    685 RQAFYISKDHNVSQTLRPITVAEEMIQELCNLLNVRslhEQQEFSLCYTVGKDKHLNYCKNDNYLMDIITESEhkklPFQ 764
Cdd:smart00295    1 VLKVYLLDGTTLEFEVDSSTTAEELLETVCRKLGIR---ESEYFGLQFEDPDEDLRHWLDPAKTLLDQDVKSE----PLT 73

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392927376    765 FYLKRTVWVHP---LRYDNAAYIdSMFDQVIDDYLRGSLIstnslgqltaATTEEIIKLAAYLF-LLLPDNPKGL----N 836
Cdd:smart00295   74 LYFRVKFYPPDpnqLKEDPTRLN-LLYLQVRNDILEGRLP----------CPEEEALLLAALALqAEFGDYDEELhdlrG 142

                           170       180       190       200       210       220
                    ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 392927376    837 AKTLPQIVPKSVIepKHRHQEEMVTRISRQLKMFGGrMRPAEAKSHFLELLSTWPTFGVLHY 898
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 392927376    394 KRKFVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIEN-RFGFLLAQYV 453
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 392927376  787 MFDQVIDDYLRGSListnslgqltAATTEEIIKLAAYLFL-LLPDNPKGLNAKT---LPQIVPKSVIepKHRHQEEMVTR 862
Cdd:cd14473     5 LYLQVKRDILEGRL----------PCSEETAALLAALALQaEYGDYDPSEHKPKylsLKRFLPKQLL--KQRKPEEWEKR 72

                          90       100
                  ....*....|....*....|....*...
gi 392927376  863 ISRQLKMFGGrMRPAEAKSHFLELLSTW 890
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 392927376   399 RALEDYVTSEVNHLSFKQGDVIELLQEPEGEtppvgnWLYGK-IENRFGF 447
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 392927376    523 FSEKPISQSLLADLGNEESKYAVETFHAIMKFMGDEPLKKSESMTDVVFKVLLICHRQPTLRDEVYCQLIKQTTSNISQk 602
Cdd:smart00139    1 YTKDPIKTSLLKLESDELQKEAVKIFKAILKFMGDIPLPRPDSHLDLVQFILQKGLDHPELRDEIYCQLIKQLTDNPSR- 79

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392927376    603 pNSALRAWRLLTIITAYFPSSLTLKPYVLQYLGDNADEWQrpFHGTARICQTNMIQTFKYGGRKVLLNALEVQQIT 678
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 392927376    685 RQAFYISKDHNVSQTLRPITVAEEMIQELCNLLNVRslhEQQEFSLCYTVGKDKHLNYCKNDNYLMDIITESEhkklPFQ 764
Cdd:smart00295    1 VLKVYLLDGTTLEFEVDSSTTAEELLETVCRKLGIR---ESEYFGLQFEDPDEDLRHWLDPAKTLLDQDVKSE----PLT 73

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392927376    765 FYLKRTVWVHP---LRYDNAAYIdSMFDQVIDDYLRGSLIstnslgqltaATTEEIIKLAAYLF-LLLPDNPKGL----N 836
Cdd:smart00295   74 LYFRVKFYPPDpnqLKEDPTRLN-LLYLQVRNDILEGRLP----------CPEEEALLLAALALqAEFGDYDEELhdlrG 142

                           170       180       190       200       210       220
                    ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 392927376    837 AKTLPQIVPKSVIepKHRHQEEMVTRISRQLKMFGGrMRPAEAKSHFLELLSTWPTFGVLHY 898
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 392927376    394 KRKFVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIEN-RFGFLLAQYV 453
Cdd:smart00326    1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSD------DGWWKGRLGRgKEGLFPSNYV 55

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 392927376  397 FVRALEDYVTSEVNHLSFKQGDVIELLQEPEGEtppvgNWLYGKIENRFGFLLAQYVD 454
Cdd:cd11843     1 PVRALYDYEGQESDELSFKAGDILTKLEEEDEQ-----GWCKGRLDGRVGLYPANYVE 53

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 392927376  787 MFDQVIDDYLRGSListnslgqltAATTEEIIKLAAYLFL-LLPDNPKGLNAKT---LPQIVPKSVIepKHRHQEEMVTR 862
Cdd:cd14473     5 LYLQVKRDILEGRL----------PCSEETAALLAALALQaEYGDYDPSEHKPKylsLKRFLPKQLL--KQRKPEEWEKR 72

                          90       100
                  ....*....|....*....|....*...
gi 392927376  863 ISRQLKMFGGrMRPAEAKSHFLELLSTW 890
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 392927376  912 EVILTINKSGIQLLQPKSKEVFKERNYDQIVSVESIRKTAYKIVRLVI---NTMQgEETLDIKTDEADEISHLIGQYM 986
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 392927376  397 FVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetPpvgNWLYGKIENRFGFLLAQYV 453
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 392927376  398 VRALEDYVTSEVNHLSFKQGDVIELLQePEgetpPVGNWLYGKIE--NRFGFLLAQYV 453
Cdd:cd11779     3 VKALYPHAAGGETQLSFEEGDVITLLG-PE----PRDGWHYGENErsGRRGWFPIAYT 55

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 392927376  396 KFVRALEDYVTSEVNHLSFKQGDVIELLQE-PEGetppvgnWLYGKIE--NRFGFLLAQYVDS 455
Cdd:cd11933     2 KSFRAMYDYRAADDDEVSFKDGDTIVNVQTiDEG-------WMYGTVQrtGKTGMLPANYVEA 57

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 392927376  397 FVRALEDYVTSEVNHLSFKQGDVIELL 423
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 392927376  400 ALEDYVTSEVNHLSFKQGDVIELLQEPEGETPPVGnWLYGKIENRFGFLLAQYV 453
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 392927376  398 VRALEDYVTSEVNHLSFKQGDVIELLQEPEGETppvgNWLYGKIENRFGFLLAQYVD 454
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 392927376   397 FVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIENRFGFLLAQYV 453
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 392927376  398 VRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIENRFGFLLAQYV 453
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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 392927376  400 ALEDYVTSEVNHLSFKQGDVIELLQEPEGetppvgNWLYGKIENRFGFLLAQYV 453
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 392927376  913 VILTINKSGIQLLQPKSKEVFKERNYDQIVSVEsirktaykivrlvINTMQGEETLDIKTDEADEISHligqYMFVTGGA 992
Cdd:cd13203    19 LILGVHCDGFKFVNPDTKEILAEYRYSDLESIL-------------VNPSDDVLTLNLSKSVPDEHKC----FMFETPQK 81

                  ....*
gi 392927376  993 EERGS 997
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 392927376  397 FVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIENRFGFLLAQYV 453
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 392927376  397 FVRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIENRFGFLLAQYV 453
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 392927376  398 VRALEDYVTSEVNHLSFKQGDVIELLQE-PEGetppvgnWLYGKIEN--RFGFLLAQYV 453
Cdd:cd11789     2 YRAMYDYAAADDDEVSFQEGDVIINVEIiDDG-------WMEGTVQRtgQSGMLPANYV 53

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

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                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 392927376  399 RALEDYVTSEVNHLSFKQGDVIELLQEPEGetppvgNWLYGKIENRFGFLLAQYVD 454
Cdd:cd11803     4 RALYDFEPENEGELGFKEGDIITLTNQIDE------NWYEGMVNGQSGFFPVNYVE 53

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

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                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 392927376  398 VRALEDYVTSEVNHLSFKQGDVIELLQEPEgetppvGNWLYGKIENRFGFLLAQYVD 454
Cdd:cd11961     2 AKALYDYDAAEDNELSFFENDKIINIEFVD------DDWWLGECHGSRGLFPSNYVE 52