Second Src Homology 3 domain of FCH and double SH3 domains protein 1; FCHSD1 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 40254312 548 LARALYSYTGQSEEELSFPEGALIRLLPRAQDGVDDGFWRGEFGGHVGVFPSLLVEEL 605
Cdd:cd11895   1 LARALYSYTGQSPEELSFPEGALIRLLPRAQDGVDDGFWRGEFGGRVGVFPSLLVEEL 58

Second Src Homology 3 domain of FCH and double SH3 domains protein 1; FCHSD1 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 40254312 548 LARALYSYTGQSEEELSFPEGALIRLLPRAQDGVDDGFWRGEFGGHVGVFPSLLVEEL 605
Cdd:cd11895   1 LARALYSYTGQSPEELSFPEGALIRLLPRAQDGVDDGFWRGEFGGRVGVFPSLLVEEL 58

Fes/CIP4, and EFC/F-BAR homology domain; Alignment extended from. Highly alpha-helical. The cytosolic endocytic adaptor proteins in fungi carry this domain at the N-terminus; several of these have been referred to as muniscin proteins. These N-terminal BAR, N-BAR, and EFC/F-BAR domains are found in proteins that regulate membrane trafficking events by inducing membrane tubulation. The domain dimerizes into a curved structure that binds to liposomes and either senses or induces the curvature of the membrane bilayer to cause biophysical changes to the shape of the bilayer; it also thereby recruits other trafficking factors, such as the GTPase dynamin. Most EFC/F-BAR domain-family members localize to actin-rich structures.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312    21 QLSILQTRQQREADLLEDIRSYSKQRAAIEREYGQALQKLAGPFLKREgqRSGEADSRTVFGAWRCLLDATVAGGQTRLQ 100
Cdd:pfam00611   1 GFKVLLKRLKQGIKLLEELASFLKERAEIEEEYAKKLQKLAKKFLKKK--KKPEDDGGTLKKAWDELLTETEQLAKQHLK 78

Variant SH3 domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 40254312   551 ALYSYTGQSEEELSFPEGALIRLLPRAqdgvDDGFWRGEFGGHVGVFPSLLVE 603
Cdd:pfam14604   1 ALYPYEPKDDDELSLQRGDVITVIEES----EDGWWEGINTGRTGLVPANYVE 49

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 40254312   473 VVFGYQAGREDELTITEGEWLEVIEEGDaDEWVKARNQHGEAGFVP 518
Cdd:pfam00018   2 ALYDYTAQEPDELSFKKGDIIIVLEKSE-DGWWKGRNKGGKEGLIP 46

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312  11 AQEVKLRFLEQLSILQTRQQREADLLEDIRSYSKQRAAIEREYGQALQKLAGPFLKREGQRSGEADSRTVfgawrcLLDA 90
Cdd:COG1196 391 ALRAAAELAAQLEELEEAEEALLERLERLEEELEELEEALAELEEEEEEEEEALEEAAEEEAELEEEEEA------LLEL 464

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312  91 TVAGGQTRLQASDRYRDLAGGTGRSAKEQVLRKGTESLQQAQAEVLQSVRELSRSRKLYG--QRQRVWALAQEKAADVqA 168
Cdd:COG1196 465 LAELLEEAALLEAALAELLEELAEAAARLLLLLEAEADYEGFLEGVKAALLLAGLRGLAGavAVLIGVEAAYEAALEA-A 543

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312 169 RLNRSDHGIFHSRTSLQKLstklsaqsAQYSQQLRAAR-NEYLLNLVATNAHLAHYYQEELPALLKVLVSELSEYLRDPL 247
Cdd:COG1196 544 LAAALQNIVVEDDEVAAAA--------IEYLKAAKAGRaTFLPLDKIRARAALAAALARGAIGAAVDLVASDLREADARY 615

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312 248 TLLGHTELEAAemILEHARHGGKATSQVNWEQDVKLFLQGPGVfsptppqqfQPAGAdqvcglewGAGGMAGESGLEKEV 327
Cdd:COG1196 616 YVLGDTLLGRT--LVAARLEAALRRAVTLAGRLREVTLEGEGG---------SAGGS--------LTGGSRRELLAALLE 676

                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312 328 QRWTSRAARDYKIQHHGHRVLQRLEQRRQQAPGREApgVEQRLQEVRENIRRAQVSQVKGAARLALLQEAGLDVQRWLKP 407
Cdd:COG1196 677 AEAELEELAERLAEEELELEEALLAEEEEERELAEA--EEERLEEELEEEALEEQLEAEREELLEELLEEEELLEEEALE 754

                       410       420       430       440
                ....*....|....*....|....*....|....*....|....*
gi 40254312 408 AMTQAQDEVEQERRLSEARLSQRDLSP---TAEDaelsDFDECEE 449
Cdd:COG1196 755 ELPEPPDLEELERELERLEREIEALGPvnlLAIE----EYEELEE 795

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of FCH and double SH3 domains proteins (FCHSD); F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. This subfamily is composed of FCH and double SH3 domain (FCHSD) proteins, so named as they contain an N-terminal F-BAR domain and two SH3 domains at the C-terminus. Vertebrates harbor two subfamily members, FCHSD1 and FCHSD2, which have been characterized only in silico. Their biological function is still unknown. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312  16 LRFLEQLSILQTRQQREADLLEDIRSYSKQRAAIEREYGQALQKLAGPFLKREGQRSGEADS------RTVFGAWRCLLD 89
Cdd:cd07654   1 LRHLEQLSKLQAKHQTECDLLEDIRTYSQKKAAIEREYGQALQKLASQFLKREWPGSGELKPeddrsgYTVWGAWLEGLD 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312  90 ATVAGGQTRLQASDRYRDLAGGTGRSAKEQVLRKGTESLQQAQAEVLQSVRELSRSRKLYGQRQRVWALAQEKAADVQAR 169
Cdd:cd07654  81 AVAQSRQNRCEAYRRYISEPAKTGRSAKEQQLKKCTEQLQRAQAEVQQTVRELSKSRKTYFEREQVAHLAREKAADVQAR 160

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312 170 LNRSDHGIFHSRTSLQKLSTKLSAQSAQYSQQLRAARNEYLLNLVATNAHLAHYYQEELPALLKVLVSELSEYLRDPLTL 249
Cdd:cd07654 161 EARSDLSIFQSRTSLQKASVKLSARKAECSSKATAARNDYLLNLAATNAHQDRYYQTDLPAIIKALDGELYDHLKDFLIS 240

                       250       260
                ....*....|....*....|....
gi 40254312 250 LGHTELEAAEMILEHARHGGKATS 273
Cdd:cd07654 241 LSHTELETAQVIQETFQRLLETSS 264

Second Src Homology 3 domain of FCH and double SH3 domains protein 1; FCHSD1 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 40254312 548 LARALYSYTGQSEEELSFPEGALIRLLPRAQDGVDDGFWRGEFGGHVGVFPSLLVEEL 605
Cdd:cd11895   1 LARALYSYTGQSPEELSFPEGALIRLLPRAQDGVDDGFWRGEFGGRVGVFPSLLVEEL 58

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 40254312 468 PCPAHVVFGYQAGREDELTITEGEWLEVIEEGDADEWVKARNQHGEAGFVPERYLNF 524
Cdd:cd11761   1 PVTCKVLYSYEAQRPDELTITEGEELEVIEDGDGDGWVKARNKSGEVGYVPENYLQF 57

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Slit-Robo GTPase Activating Proteins; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. 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, all of which are expressed during embryonic and early development in the nervous system but with different localization and timing. srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312  17 RFLEQLSILQTRQQREADLLEDIRSYSKQRAAIEREYGQALQKLAGPF---LKREGQRSGEADSRTVFGAWRCLLDatva 93
Cdd:cd07656   2 QLSEQLKCLDLRTEAQVQLLADLQDYFRRRAEIELEYSRSLEKLADRFsskHKNEKSKREDWSLLSPVNCWNTLLV---- 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312  94 ggQTRLQA------SDRYR--------DLAGGTGRSAKeqvlrKGTESLQQAQAEVLQSVRELSRSRKLYGQRQRVWALA 159
Cdd:cd07656  78 --QTKQESrdhstlSDIYSnnlvqrlgQMSEDLQRISK-----KCREIGSQLHDELLRVLNELQTAMKTYHTYHAESKSA 150

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312 160 Q------EKAADVQARLNRSDHGIFHSRTSLQKLSTKlsaQSAQYSQ-QLRA--ARNEYLLNLVATNAHLAHYYQEELPA 230
Cdd:cd07656 151 ErklkeaEKQEEKQEQSPEKKLERSRSSKKIEKEVEK---RQAKYSEaKLKCtkARNEYLLNLAAANATIHKYFVQDLSD 227

                ..
gi 40254312 231 LL 232
Cdd:cd07656 228 LI 229

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Slit-Robo GTPase Activating Protein 1; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. 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, also called Rho GTPase-Activating Protein 13 (ARHGAP13), is a Cdc42- and RhoA-specific GAP and is expressed later in the development of CNS (central nervous system) tissues. It is an important downstream signaling molecule of Robo1. srGAP1 contains an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312  17 RFLEQLSILQTRQQREADLLEDIRSYSKQRAAIEREYGQALQKLAGPFL------KREGQRSGEADSRTVFGAWRCLLDA 90
Cdd:cd07683   2 QLVEQQKCLEQQTEMRVQLLQDLQDFFRKKAEIESEYSRNLEKLAERFMaktrstKDHQQYKKDQNLLSPVNCWYLLLNQ 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312  91 TVAGGQTRLQASDRYRDLAGGTGRSAKE---QVLRKGTESLQQAQAEVLQSVRELSRSRKLYG--QRQRVWALAQEKAAD 165
Cdd:cd07683  82 VRRESKDHATLSDIYLNNVIMRFMQISEdstRMFKKSKEIAFQLHEDLMKVLNELYTVMKTYHmyHTESISAESKLKEAE 161

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312 166 VQA--RLNRSDHGIFHSRTS-----------LQKLSTKLSAQSAQYSQQLRAARNEYLLNLVATNAHLAHYYQEELPALL 232
Cdd:cd07683 162 KQEekQIGRSGDPVFHIRLEdrhqrrssvkkIEKMKEKRQAKYSENKLKSIKARNEYLLTLEATNASVFKYYIHDLSDLI 241

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Cdc42-Interacting Protein 4 and similar proteins; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. This subfamily is composed of Cdc42-Interacting Protein 4 (CIP4), Formin Binding Protein 17 (FBP17), FormiN Binding Protein 1-Like (FNBP1L), and similar proteins. CIP4 and FNBP1L are Cdc42 effectors that bind Wiskott-Aldrich syndrome protein (WASP) and function in endocytosis. CIP4 and FBP17 bind to the Fas ligand and may be implicated in the inflammatory response. CIP4 may also play a role in phagocytosis. Members of this subfamily typically contain an N-terminal F-BAR domain and a C-terminal SH3 domain. In addition, some members such as FNBP1L contain a central Cdc42-binding HR1 domain. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312  21 QLSILQTRQQREADLLEDIRSYSKQRAAIEREYGQALQKLAGPFLKRegQRSGEADSRTVFGAWRCLLDATVA-GGQTRL 99
Cdd:cd07653   6 QFDNLEKHTQKGIDFLERYGKFVKERAAIEQEYAKKLRKLVKKYLPK--KKEEDEYSFSSVKAFRSILNEVNDiAGQHEL 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312 100 QASDRYRDLAGGTGRSAKEQ-VLRKGTES-LQQAQAEVLQSVRELSRSRKLYGQRQRVWALAQEKAADVQARLNrsdhgi 177
Cdd:cd07653  84 IAENLNSNVCKELKTLISELrQERKKHLSeGSKLQQKLESSIKQLEKSKKAYEKAFKEAEKAKQKYEKADADMN------ 157

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 40254312 178 fHSRTSLQKLStklsAQSAQYSQQLRAARNEYLLNLVATNAHLAHYYQEELPALLKVL 235
Cdd:cd07653 158 -LTKADVEKAK----ANANLKTQAAEEAKNEYAAQLQKFNKEQRQHYSTDLPQIFDKL 210

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 40254312    546 AFLARALYSYTGQSEEELSFPEGALIRLLpraqDGVDDGFWRGEFG-GHVGVFPSLLVE 603
Cdd:smart00326   2 GPQVRALYDYTAQDPDELSFKKGDIITVL----EKSDDGWWKGRLGrGKEGLFPSNYVE 56

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 40254312 549 ARALYSYTGQSEEELSFPEGALIRLLPRaqdgVDDGFWRGEFGGH-VGVFPSLLVEE 604
Cdd:cd11825   2 VKALYDYRAQRPDELSFCKHAIITNVEK----EDGGWWRGDYGGKkQKWFPANYVEE 54

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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 40254312 549 ARALYSYTGQSEEELSFPEGALIRLLpraqDGVDDGFWRGEFGGHVGVFPSLLVEE 604
Cdd:cd11961   2 AKALYDYDAAEDNELSFFENDKIINI----EFVDDDWWLGECHGSRGLFPSNYVEL 53

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 40254312 549 ARALYSYTGQSEEELSFPEGALIRLLpraqDGVDDGFWRGEFGGHVGVFPSLLVEE 604
Cdd:cd11874   2 CKVLFSYTPQNEDELELKVGDTIEVL----GEVEEGWWEGKLNGKVGVFPSNFVKE 53

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 40254312 549 ARALYSYTGQSEEELSFPEGALIRLLPRaqDGVDDGFWRGEFGGHVGVFPSLLVEE 604
Cdd:cd11875   2 ARVLFDYEAENEDELTLREGDIVTILSK--DCEDKGWWKGELNGKRGVFPDNFVEP 55

Src Homology 3 domain of Cdc42-Interacting Protein 4; This subfamily is composed of Cdc42-Interacting Protein 4 (CIP4), Formin Binding Protein 17 (FBP17), FormiN Binding Protein 1-Like (FNBP1L), and similar proteins. CIP4 and FNBP1L are Cdc42 effectors that bind Wiskott-Aldrich syndrome protein (WASP) and function in endocytosis. CIP4 and FBP17 bind to the Fas ligand and may be implicated in the inflammatory response. CIP4 may also play a role in phagocytosis. It functions downstream of Cdc42 in PDGF-dependent actin reorganization and cell migration, and also regulates the activity of PDGFRbeta. It uses Src as a substrate in regulating the invasiveness of breast tumor cells. CIP4 may also play a role in the pathogenesis of Huntington's disease. Members of this subfamily typically contain an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain, a central Cdc42-binding HR1 domain, and a C-terminal SH3 domain. The SH3 domain of CIP4 associates with Gapex-5, a Rab31 GEF. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 40254312 473 VVFGYQAGREDELTITEGEWLEVIEEGDADEWVKARNQHGEAGFVPERYLNF 524
Cdd:cd11911   4 ALYDFDGTSEGTLSMEEGEILLVLEEDGGDGWTRVRKNNGDEGYVPTSYIEV 55

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.

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                ....*....|....*....|....*....|....*....|....*....|....*..
gi 40254312 548 LARALYSYTGQSEEELSFPEGALIRLLpRAQDGvddGFWRGEFGGHVGVFPSLLVEE 604
Cdd:cd11877   1 LVRAKFNFEGTNEDELSFDKGDIITVT-QVVEG---GWWEGTLNGKTGWFPSNYVKE 53

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 40254312 550 RALYSYTGQSEEELSFPEGALIRLlpraQDGVDDGFWRGEFGGHVGVFPSLLVEE 604
Cdd:cd11772   3 RALYDYEAQHPDELSFEEGDLLYI----SDKSDPNWWKATCGGKTGLIPSNYVEE 53

Src Homology 3 domain of Epidermal growth factor receptor kinase substrate 8 and similar proteins; This group is composed of Eps8 and Eps8-like proteins including Eps8-like 1-3, among others. These proteins contain N-terminal Phosphotyrosine-binding (PTB), central SH3, and C-terminal effector domains. Eps8 binds either Abi1 (also called E3b1) or Rab5 GTPase activating protein RN-tre through its SH3 domain. With Abi1 and Sos1, it becomes part of a trimeric complex that is required to activate Rac. Together with RN-tre, it inhibits the internalization of EGFR. The SH3 domains of Eps8 and similar proteins recognize peptides containing a PxxDY motif, instead of the classical PxxP motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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                ....*....|....*....|....*....|....*....|....*...
gi 40254312 471 AHVVFGYQAGREDELTITEGEWLEVIEegDADEWVKARNQHGEAGFVP 518
Cdd:cd11764   2 VRVLYDFTARNSKELSVLKGEYLEVLD--DSRQWWKVRNSRGQVGYVP 47

The Extended FES-CIP4 Homology (FCH) or F-BAR (FCH and Bin/Amphiphysin/Rvs) domain, a dimerization module that binds and bends membranes; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. F-BAR domain containing proteins, also known as Pombe Cdc15 homology (PCH) family proteins, include Fes and Fer tyrosine kinases, PACSINs/Syndapins, FCHO, PSTPIP, CIP4-like proteins and srGAPs. Many members also contain an SH3 domain and play roles in endocytosis. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules. These tubules have diameters larger than those observed with N-BARs. The F-BAR domains of some members such as NOSTRIN and Rgd1 are important for the subcellular localization of the protein.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312  25 LQTRQQREADLLEDIRSYSKQRAAIEREYGQALQKLAGPFLKreGQRSGEADSRTVFGAWRclldatvaggQTRLQASDR 104
Cdd:cd07610   5 LEKRTELGLDLLKDLREFLKKRAAIEEEYAKNLQKLAKKFSK--KPESGKTSLGTSWNSLR----------EETESAATV 72

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 40254312 105 YRDLAggtgrSAKEQVLRKGTESLQQAQAEvlQSVRELSRSRKLYGQRQRVWALAQEKAADVqarlnrsdhgifhSRTSL 184
Cdd:cd07610  73 HEELS-----EKLSQLIREPLEKVKEDKEQ--ARKKELAEGEKLKKKLQELWAKLAKKADEE-------------YREQV 132

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 40254312 185 QKLSTklsaqsaqysqqlraARNEYLLNLVATNAHLAHYY---QEELPALLKVLVSELSEYL 243
Cdd:cd07610 133 EKLNP---------------AQSEYEEEKLNKIQAEQEREeerLEILKDNLKNYINAIKEIP 179

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

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                ....*....|....*....|....*....|....*....|....*....|....
gi 40254312 550 RALYSYTGQSEEELSFPEGALIRLLPRAqdgvDDGFWRGEFGGHVGVFPSLLVE 603
Cdd:cd11826   3 VALYDYTADKDDELSFQEGDIIYVTKKN----DDGWYEGVLNGVTGLFPGNYVE 52

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

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                ....*....|....*....|....*....|....*....|....*....|...
gi 40254312 551 ALYSYTGQSEEELSFPEGALIRLLPRAqdgvDDGFWRGEFGGHVGVFPSLLVE 603
Cdd:cd11995   5 GMYDYTAQNDDELAFSKGQIINVLNKE----DPDWWKGELNGQVGLFPSNYVK 53

Src Homology 3 domain of Formin Binding Protein 1-Like; FormiN Binding Protein 1-Like (FNBP1L), also known as Toca-1 (Transducer of Cdc42-dependent actin assembly), forms a complex with neural Wiskott-Aldrich syndrome protein (N-WASP). The FNBP1L/N-WASP complex induces the formation of filopodia and endocytic vesicles. FNBP1L is required for Cdc42-induced actin assembly and is essential for autophagy of intracellular pathogens. It contains an N-terminal F-BAR domain, a central Cdc42-binding HR1 domain, and a C-terminal SH3 domain. The SH3 domain of the related protein, CIP4, associates with Gapex-5, a Rab31 GEF. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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                ....*....|....*....|....*....|....*....|....*....|
gi 40254312 474 VFGYQAGREDELTITEGEWLEVIEEGDADEWVKARNQHGEAGFVPERYLN 523
Cdd:cd12072   6 LYPFDGSNEGTLAMKEGEVLYIIEEDKGDGWTRARKQNGEEGYVPTSYIE 55

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

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                ....*....|....*....|....*....|....*....|....*....|....*.
gi 40254312 550 RALYSYTGQSEEELSFPEGALIRLLprAQDGVDDGFWRGEFGGHVGVFPSLLVEEL 605
Cdd:cd12057   3 KVLFPYEAQNEDELTIKEGDIVTLI--SKDCIDAGWWEGELNGRRGVFPDNFVKLL 56

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

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                ....*....|....*....|....*....|....*....|....*....|....*.
gi 40254312 549 ARALYSYTGQSEEELSFPEGALIRLLPRAQDgvdDGFWRGEFGGHVGVFPSLLVEE 604
Cdd:cd11830   2 AKARYDFCARDMRELSLKEGDVVKIYNKKGQ---QGWWRGEINGRIGWFPSTYVEE 54

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.

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                ....*....|....*....|....*....|....*....|....*....|....*..
gi 40254312 548 LARALYSYTGQSEEELSFPEGALIRLLpraqDGVDDGFWRGEFGGHVGVFPSLLVEE 604
Cdd:cd11805   1 RVQALYDFNPQEPGELEFRRGDIITVL----DSSDPDWWKGELRGRVGIFPANYVQP 53

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 40254312 550 RALYSYTGQSEEELSFPEGALIRLLPRaqdgVDDGFWRGEFGGHVG-VFPSLLVEEL 605
Cdd:cd11969   3 KALYDYRAKRSDELSFCKGALIHNVSK----ETGGWWKGDYGGKVQhYFPSNYVEDV 55

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 40254312 549 ARALYSYTGQSEEELSFPEGALIRLLpraqDGVDDGFWRGEFGGHVGVFPSLLVE 603
Cdd:cd11959   2 AVALYDYQAADDDEISFDPDDIITNI----EMIDEGWWRGVCRGKYGLFPANYVE 52

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

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                ....*....|....*....|....*....|....*....|....*....|
gi 40254312 549 ARALYSYTGQSEEELSFPEGALIRLLpraqDGVDDGFWRGEFGGHVGVFP 598
Cdd:cd11818   2 ARALYDFTGENEDELSFKAGDIITEL----ESIDEEWMSGELRGKSGIFP 47