Ephexin Pleckstrin homology (PH) domain; Ephexin-1 (also called NGEF/ neuronal guanine nucleotide exchange factor) plays a role in the homeostatic modulation of presynaptic neurotransmitter release. Specific functions are still unknown for Ephexin-2 (also called RhoGEF19) and Ephexin-3 (also called Rho guanine nucleotide exchange factor 5/RhoGEF5, Transforming immortalized mammary oncogene/p60 TIM, and NGEF/neuronalGEF). Ephexin-4 (also called RhoGEF16) acts downstream of EphA2 to promote ligand-independent breast cancer cell migration and invasion toward epidermal growth factor through activation of RhoG. This in turn results in the activation of RhoG which recruits ELMO2 and Dock4 to form a complex with EphA2 at the tips of cortactin-rich protrusions in migrating breast cancer cells. Ephexin-5 is the specific GEF for RhoA activation and the regulation of vascular smooth muscle contractility. It interacts with EPHA4 PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. The members of the Ephexin family contains a RhoGEF (DH) followed by a PH domain and an SH3 domain. The ephexin PH domain is believed to act with the DH domain in mediating protein-protein interactions. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912 580 EGKIFPLISQARWLVRHGELVELAPLPAAPPAKLKLSSKAVYLHLFNDCLLLSRRKELGKFAVFVHANMAELQVRDLSLK 659
Cdd:cd01221    1 KIKAFPLISSSRWLVKRGELTELVEDGGSLTFRKKFSKTPVYLFLFNDLLLITKKKSEERYLVLDYAPRNLVQVEEVEDP 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 568930912 660 LQGIPG---HVFLLRLLHGQRAR-HQLLLRARTESEKQRWISALRPSSPQE 706
Cdd:cd01221   81 LQLPQPlgkNLFLLTLLENHEGKtVELLLSAESESDRERWLSALSPPKSEL 131

Ephexin Pleckstrin homology (PH) domain; Ephexin-1 (also called NGEF/ neuronal guanine nucleotide exchange factor) plays a role in the homeostatic modulation of presynaptic neurotransmitter release. Specific functions are still unknown for Ephexin-2 (also called RhoGEF19) and Ephexin-3 (also called Rho guanine nucleotide exchange factor 5/RhoGEF5, Transforming immortalized mammary oncogene/p60 TIM, and NGEF/neuronalGEF). Ephexin-4 (also called RhoGEF16) acts downstream of EphA2 to promote ligand-independent breast cancer cell migration and invasion toward epidermal growth factor through activation of RhoG. This in turn results in the activation of RhoG which recruits ELMO2 and Dock4 to form a complex with EphA2 at the tips of cortactin-rich protrusions in migrating breast cancer cells. Ephexin-5 is the specific GEF for RhoA activation and the regulation of vascular smooth muscle contractility. It interacts with EPHA4 PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. The members of the Ephexin family contains a RhoGEF (DH) followed by a PH domain and an SH3 domain. The ephexin PH domain is believed to act with the DH domain in mediating protein-protein interactions. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912 580 EGKIFPLISQARWLVRHGELVELAPLPAAPPAKLKLSSKAVYLHLFNDCLLLSRRKELGKFAVFVHANMAELQVRDLSLK 659
Cdd:cd01221    1 KIKAFPLISSSRWLVKRGELTELVEDGGSLTFRKKFSKTPVYLFLFNDLLLITKKKSEERYLVLDYAPRNLVQVEEVEDP 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 568930912 660 LQGIPG---HVFLLRLLHGQRAR-HQLLLRARTESEKQRWISALRPSSPQE 706
Cdd:cd01221   81 LQLPQPlgkNLFLLTLLENHEGKtVELLLSAESESDRERWLSALSPPKSEL 131

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912   382 FELITSEASYIHSLSVAVGHFLGSVELSECLGTQDK-QWLFSKLPEVKSTSERFLHDLEQRL-EADVLRFSVCDVVLHHC 459
Cdd:smart00325   3 KELLQTERNYVRDLKLLVEVFLKPLKKELKLLSPNElETLFGNIEEIYEFHRDFLDELEERIeEWDDSVERIGDVFLKLE 82

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912   460 PAFRrVYLPYVTNQAYQERTYQRLLlENPKFPGILARLEESPVCQRLPLTSFLILPFQRVTRLKMLVENILKRTAPGSQD 539
Cdd:smart00325  83 EFFK-IYSEYCSNHPDALELLKKLK-KNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELLKHTPEDHED 160

                          170       180
                   ....*....|....*....|
gi 568930912   540 EDMATKAFSALKELVQECNA 559
Cdd:smart00325 161 REDLKKALKAIKELANQVNE 180

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912  370 LSLRDCKLQEAKFELITSEASYIHSLSVAVGHFLGSVELSECLGTQDKQ----WLFSKLPEVKSTSERFLHDLEQRLEAD 445
Cdd:COG5422   478 LPKQEIKRQEAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPENARRnfikHVFANINEIYAVNSKLLKALTNRQCLS 557

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912  446 VLRFSVCDVVLHHCPAFRRvYLPYVTNQAYQERTYQRLLLENPKFPGILARLEESPVCQRLPLTSFLILPFQRVTRLKML 525
Cdd:COG5422   558 PIVNGIADIFLDYVPKFEP-FIKYGASQPYAKYEFEREKSVNPNFARFDHEVERLDESRKLELDGYLTKPTTRLARYPLL 636

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....
gi 568930912  526 VENILKRTAPGSQDEDMATKAFSALKELVQECNASVQSMKRTEELIHLSKKIHF 579
Cdd:COG5422   637 LEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESGKAENRGDLFHLNQQLLF 690

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912   618 KAVYLHLFNDCLLLSRRKELGKFAVFVHA-NMAELQVRDLSLKLQGIPGHVFLLRLlhgqRARHQLLLRARTESEKQRWI 696
Cdd:smart00233  19 KKRYFVLFNSTLLYYKSKKDKKSYKPKGSiDLSGCTVREAPDPDSSKKPHCFEIKT----SDRKTLLLQAESEEEREKWV 94

                   ....
gi 568930912   697 SALR 700
Cdd:smart00233  95 EALR 98

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912  593 LVRHGELVELAPLPAAppaklklSSKAVYLHLFNDCLLLSRRKELGKFAVFVHA-NMAELQVRDLSLKLQGIPGHVFLLR 671
Cdd:pfam00169   1 VVKEGWLLKKGGGKKK-------SWKKRYFVLFDGSLLYYKDDKSGKSKEPKGSiSLSGCEVVEVVASDSPKRKFCFELR 73

                          90       100
                  ....*....|....*....|....*....
gi 568930912  672 LLHGQRARhQLLLRARTESEKQRWISALR 700
Cdd:pfam00169  74 TGERTGKR-TYLLQAESEEERKDWIKAIQ 101

Ephexin Pleckstrin homology (PH) domain; Ephexin-1 (also called NGEF/ neuronal guanine nucleotide exchange factor) plays a role in the homeostatic modulation of presynaptic neurotransmitter release. Specific functions are still unknown for Ephexin-2 (also called RhoGEF19) and Ephexin-3 (also called Rho guanine nucleotide exchange factor 5/RhoGEF5, Transforming immortalized mammary oncogene/p60 TIM, and NGEF/neuronalGEF). Ephexin-4 (also called RhoGEF16) acts downstream of EphA2 to promote ligand-independent breast cancer cell migration and invasion toward epidermal growth factor through activation of RhoG. This in turn results in the activation of RhoG which recruits ELMO2 and Dock4 to form a complex with EphA2 at the tips of cortactin-rich protrusions in migrating breast cancer cells. Ephexin-5 is the specific GEF for RhoA activation and the regulation of vascular smooth muscle contractility. It interacts with EPHA4 PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. The members of the Ephexin family contains a RhoGEF (DH) followed by a PH domain and an SH3 domain. The ephexin PH domain is believed to act with the DH domain in mediating protein-protein interactions. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912 580 EGKIFPLISQARWLVRHGELVELAPLPAAPPAKLKLSSKAVYLHLFNDCLLLSRRKELGKFAVFVHANMAELQVRDLSLK 659
Cdd:cd01221    1 KIKAFPLISSSRWLVKRGELTELVEDGGSLTFRKKFSKTPVYLFLFNDLLLITKKKSEERYLVLDYAPRNLVQVEEVEDP 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 568930912 660 LQGIPG---HVFLLRLLHGQRAR-HQLLLRARTESEKQRWISALRPSSPQE 706
Cdd:cd01221   81 LQLPQPlgkNLFLLTLLENHEGKtVELLLSAESESDRERWLSALSPPKSEL 131

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912   382 FELITSEASYIHSLSVAVGHFLGSVELSECLGTQDK-QWLFSKLPEVKSTSERFLHDLEQRL-EADVLRFSVCDVVLHHC 459
Cdd:smart00325   3 KELLQTERNYVRDLKLLVEVFLKPLKKELKLLSPNElETLFGNIEEIYEFHRDFLDELEERIeEWDDSVERIGDVFLKLE 82

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912   460 PAFRrVYLPYVTNQAYQERTYQRLLlENPKFPGILARLEESPVCQRLPLTSFLILPFQRVTRLKMLVENILKRTAPGSQD 539
Cdd:smart00325  83 EFFK-IYSEYCSNHPDALELLKKLK-KNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELLKHTPEDHED 160

                          170       180
                   ....*....|....*....|
gi 568930912   540 EDMATKAFSALKELVQECNA 559
Cdd:smart00325 161 REDLKKALKAIKELANQVNE 180

Src homology 3 domain of ephexin-1-like SH3 domain containing Rho guanine nucleotide exchange factors; Members of this family contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and C-terminal SH3 domains. They include the Rho guanine nucleotide exchange factors ARHGEF5, ARHGEF16, ARHGEF19, ARHGEF26, ARHGEF27 (also called ephexin-1), and similar proteins, and are also called ephexins because they interact directly with ephrin A receptors. GEFs interact with Rho GTPases via their DH domains to catalyze nucleotide exchange by stabilizing the nucleotide-free GTPase intermediate. They play important roles in neuronal development. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH 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 568930912 719 QVQCVRTYKALQPDELTLEKTDILAVKTRTSDGWLEGVRLADGEKGWVPQAHVVE 773
Cdd:cd11793    1 QVQCVHAYTAQQPDELTLEEGDVVNVLRKMPDGWYEGERLRDGERGWFPSSYTEE 55

Src homology 3 domain of the Rho guanine nucleotide exchange factors ARHGEF16 and ARHGEF26; ARHGEF16, also called ephexin-4, acts as a GEF for RhoG, activating it by exchanging bound GDP for free GTP. RhoG is a small GTPase that is a crucial regulator of Rac in migrating cells. ARHGEF16 interacts directly with the ephrin receptor EphA2 and mediates cell migration and invasion in breast cancer cells by activating RhoG. ARHGEF26, also called SGEF (SH3 domain-containing guanine exchange factor), also activates RhoG. It is highly expressed in liver and may play a role in regulating membrane dynamics. ARHGEF16 and ARHGEF26 contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and SH3 domains. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH 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
                 ....*....|....*....|....*....|....*....|....*....
gi 568930912 719 QVQCVRTYKALQPDELTLEKTDILAVKTRTSDGWLEGVRLADGEKGWVP 767
Cdd:cd11938    1 QVEIIKAYTAKQPDELSLQQADVVLVLQTESDGWYYGERLRDGERGWFP 49

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 568930912   716 DRPQVQCVRTYKALQPDELTLEKTDILAVKTRTSDGWLEGvRLADGEKGWVPQAHV 771
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKG-RLGRGKEGLFPSNYV 55

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912   618 KAVYLHLFNDCLLLSRRKELGKFAVFVHA-NMAELQVRDLSLKLQGIPGHVFLLRLlhgqRARHQLLLRARTESEKQRWI 696
Cdd:smart00233  19 KKRYFVLFNSTLLYYKSKKDKKSYKPKGSiDLSGCTVREAPDPDSSKKPHCFEIKT----SDRKTLLLQAESEEEREKWV 94

                   ....
gi 568930912   697 SALR 700
Cdd:smart00233  95 EALR 98

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 568930912 725 TYKALQPDELTLEKTDILAVKTRTSDGWLEGVrlADGEKGWVPQAHVVE 773
Cdd:cd11766    7 NYEAQREDELSLRKGDRVLVLEKSSDGWWRGE--CNGQVGWFPSNYVTE 53

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568930912  593 LVRHGELVELAPLPAAppaklklSSKAVYLHLFNDCLLLSRRKELGKFAVFVHA-NMAELQVRDLSLKLQGIPGHVFLLR 671
Cdd:pfam00169   1 VVKEGWLLKKGGGKKK-------SWKKRYFVLFDGSLLYYKDDKSGKSKEPKGSiSLSGCEVVEVVASDSPKRKFCFELR 73

                          90       100
                  ....*....|....*....|....*....
gi 568930912  672 LLHGQRARhQLLLRARTESEKQRWISALR 700
Cdd:pfam00169  74 TGERTGKR-TYLLQAESEEERKDWIKAIQ 101

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 568930912 719 QVQCVRTYKALQPDELTLEKTDILAVKTRTSDGWLEGVrlADGEKGWVPQAHVVE 773
Cdd:cd11877    1 LVRAKFNFEGTNEDELSFDKGDIITVTQVVEGGWWEGT--LNGKTGWFPSNYVKE 53

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 568930912 720 VQCVRTYKALQPDELTLEKTDILAVKTRTSDGWLEGVrlADGEKGWVPQAHV 771
Cdd:cd11826    2 VVALYDYTADKDDELSFQEGDIIYVTKKNDDGWYEGV--LNGVTGLFPGNYV 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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 568930912 725 TYKALQPDELTLEKTDILAVKTRTSDGWLEGVrlADGEKGWVPQAHVVE 773
Cdd:cd11772    7 DYEAQHPDELSFEEGDLLYISDKSDPNWWKAT--CGGKTGLIPSNYVEE 53

Second Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 568930912 726 YKALQPDELTLEKTDILAVKTRTSDGWLEGVRlaDGEKGWVPQAHVVE 773
Cdd:cd11902    9 YVAEREDELSLVKGSRVTVMEKCSDGWWRGSY--NGQIGWFPSNYVVE 54

Second N-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin and key regulatory proteins of the actin cytoskeleton. It plays an important role in regulating cell junction configuration. The four N-terminal SH3 domains of DNMBP binds the GTPase dynamin, which plays an important role in the fission of endocytic vesicles. 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 568930912 722 CVRTYKALQPDELTLEKTDILAVKTRTSDGWLEGvRLADGEKGWVPQAHVVE 773
Cdd:cd11795    4 CIEAFTSQEPGHLNLQRGDLVELTGTTDSGWLQG-RSCWGSSGFFPSSCVQE 54

Src Homology 3 domain of Amphiphysin and related domains; Amphiphysins function primarily in endocytosis and other membrane remodeling events. They exist in several isoforms and mammals possess two amphiphysin proteins from distinct genes. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin, and synaptojanin. They function in synaptic vesicle endocytosis. Human autoantibodies to amphiphysin I hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy. Amphiphysins contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. The SH3 domain of amphiphysins bind proline-rich motifs present in binding partners such as dynamin, synaptojanin, and nsP3. It also belongs to a subset of SH3 domains that bind ubiquitin in a site that overlaps with the peptide binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 568930912 720 VQCVRTYKALQPDELTLEKTDILAV-----KTRTSDGWLEGVRLADGEKGWVP 767
Cdd:cd11790    5 VRATHDYTAEDTDELTFEKGDVILVipfddPEEQDEGWLMGVKESTGCRGVFP 57

C-terminal (or second) Src Homology 3 domain of the p67phox subunit of NADPH oxidase; p67phox, also called Neutrophil cytosol factor 2 (NCF-2), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox plays a regulatory role and contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. It binds, via its C-terminal SH3 domain, to a proline-rich region of p47phox and upon activation, this complex assembles with flavocytochrome b558, the Nox2-p22phox heterodimer. Concurrently, RacGTP translocates to the membrane and interacts with the TPR domain of p67phox, which leads to the activation of NADPH oxidase. The PB1 domain of p67phox binds to its partner PB1 domain in p40phox, and this facilitates the assembly of p47phox-p67phox at the membrane. 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 568930912 719 QVQCVRTYKALQPDELTLEKTDILAVKTRTSDGWLEGVrlADGEKGWVPQAHVVE 773
Cdd:cd12046    1 QVVALFSYEASQPEDLEFQKGDVILVLSKVNEDWLEGQ--CKGKIGIFPSAFVED 53

Second Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 568930912 725 TYKALQPDELTLEKTDILAVKTRTSDGWLEGVRlaDGEKGWVPQAHVVE 773
Cdd:cd11901    9 NYTAEREDELSLVKGTKVIVMEKCSDGWWRGSY--NGQVGWFPSNYVTE 55

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains 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.

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gi 568930912 726 YKALQPDELTLEKTDILAVKTRTSDGWLEG-VRladGEKGWVPQAHVVE 773
Cdd:cd11823    8 YTANREDELSLQPGDIIEVHEKQDDGWWLGeLN---GKKGIFPATYVEE 53

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

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gi 568930912 616 SSKAVYLHLFNDCLLLSRRKELGKFAVFVHANMAE-LQVRDLSlklQGIPGHVFLLRLLHGQRarhqLLLRARTESEKQR 694
Cdd:cd00821   15 SWKKRWFVLFEGVLLYYKSKKDSSYKPKGSIPLSGiLEVEEVS---PKERPHCFELVTPDGRT----YYLQADSEEERQE 87

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gi 568930912 695 WISAL 699
Cdd:cd00821   88 WLKAL 92

Src Homology 3 domain of alpha-Pak Interactive eXchange factor; Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6) or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. 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 568930912 726 YKALQPDELTLEKTDILAVKTRTSDGWLEGVrlADGEKGWVPQAHVVEISS 776
Cdd:cd12060   10 FKQTNEDELSVCKGDIIYVTRVEEGGWWEGT--LNGKTGWFPSNYVREIKS 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.

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gi 568930912 726 YKALQPDELTLEKTDILAV-KTRTSDGWLEGvRLADGEKGWVPQAHV 771
Cdd:cd11761   10 YEAQRPDELTITEGEELEViEDGDGDGWVKA-RNKSGEVGYVPENYL 55

Src homology 3 domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; PSTPIP1, also called CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, 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 568930912 726 YKALQPDELTLEKTDILAVKTRTSDGWLEGVRlaDGEKGWVPQAHV 771
Cdd:cd11824    8 YTAQEDDELSISKGDVVAVIEKGEDGWWTVER--NGQKGLVPGTYL 51

Src Homology 3 domain of Nephrocystin (or Nephrocystin-1); Nephrocystin contains an SH3 domain involved in signaling pathways that regulate cell adhesion and cytoskeletal organization. It is a protein that in humans is associated with juvenile nephronophthisis, an inherited kidney disease characterized by renal fibrosis that lead to chronic renal failure in children. It is localized in cell-cell junctions in renal duct cells, and is known to interact with Ack1, an activated Cdc42-associated kinase. 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 568930912 726 YKALQPDELTLEKTDILAVKTRTSDGWLEGVRlADGEKGWVP 767
Cdd:cd11770    8 FQAEQEGDLSFKKGEVLRIISKRADGWWLAEN-SKGNRGLVP 48

Src Homology 3 domain of Ras GTPase-Activating Protein 1; RasGAP, also called Ras p21 protein activator, RASA1, or p120RasGAP, is part of the GAP1 family of GTPase-activating proteins. It is a 120kD cytosolic protein containing an SH3 domain flanked by two SH2 domains at the N-terminal end, a pleckstrin homology (PH) domain, a calcium dependent phospholipid binding domain (CaLB/C2), and a C-terminal catalytic GAP domain. It stimulates the GTPase activity of normal RAS p21. It acts as a positive effector of Ras in tumor cells. It also functions as a regulator downstream of tyrosine receptors such as those of PDGF, EGF, ephrin, and insulin, among others. The SH3 domain of RasGAP is unable to bind proline-rich sequences but have been shown to interact with protein partners such as the G3BP protein, Aurora kinases, and the Calpain small subunit 1. The RasGAP SH3 domain is necessary for the downstream signaling of Ras and it also influences Rho-mediated cytoskeletal reorganization. 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 568930912 717 RPQVQCVRTY-KALQPDELTLEKTDILAVKTRTSDGWLEGVRLADGEKGWVPQAHVVEI 774
Cdd:cd11788    1 RRRVRAILPYnKVPDTDELSFQKGDIFVVHNELEDGWLWVTSLRTGESGLVFRDLVEEL 59

Third Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle, of SH3RF3. 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 568930912 726 YKALQPDELTLEKTDILAVKTRTSDGWLEGVRLADGEKGWVPQAHVVEI 774
Cdd:cd11925    9 YKPQKNDELELRKGEMYRVIEKCQDGWFKGTSLRTGVSGVFPGNYVTPV 57