RhoGAP: GTPase-activator protein (GAP) for Rho-like GTPases; GAPs towards Rho/Rac/Cdc42-like small GTPases. Small GTPases (G proteins) cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when bound to GDP. The Rho family of small G proteins, which includes Cdc42Hs, activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. G proteins generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude. The RhoGAPs are one of the major classes of regulators of Rho G proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 328 MDGREPVYNSNKDSQS--EGTAQLDSIGFSIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETETDIC 405
Cdd:cd04374     1 MDGKEPVYHSPGRLQSevEGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKTSTPGDVDLD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 406 A-EWEIKTITSALKTYLRMLPGPLMMYQFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAKENRYNQK 484
Cdd:cd04374    81 NsEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

RhoGAP_Graf: GTPase-activator protein (GAP) domain for Rho-like GTPases found in GRAF (GTPase regulator associated with focal adhesion kinase); Graf is a multi-domain protein, containing SH3 and PH domains, that binds focal adhesion kinase and influences cytoskeletal changes mediated by Rho proteins. Graf exhibits GAP activity toward RhoA and Cdc42, but only weakly activates Rac1. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 328 MDGREPVYNSNKDSQS--EGTAQLDSIGFSIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETETDIC 405
Cdd:cd04374     1 MDGKEPVYHSPGRLQSevEGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKTSTPGDVDLD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 406 A-EWEIKTITSALKTYLRMLPGPLMMYQFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAKENRYNQK 484
Cdd:cd04374    81 NsEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

GTPase Regulator Associated with Focal adhesion and related proteins Pleckstrin homology (PH) domain; This hierarchy contains GRAF family members: OPHN1/oligophrenin1, GRAF1 (also called ARHGAP26/Rho GTPase activating protein 26), GRAF2 (also called ARHGAP10/ARHGAP42), AK057372, and LOC129897, all of which are members of the APPL family. OPHN1 is a RhoGAP involved in X-linked mental retardation, epilepsy, rostral ventricular enlargement, and cerebellar hypoplasia. Affected individuals have morphological abnormalities of their brain with enlargement of the cerebral ventricles and cerebellar hypoplasia. OPHN1 negatively regulates RhoA, Cdc42, and Rac1 in neuronal and non-neuronal cells. GRAF1 sculpts the endocytic membranes of the CLIC/GEEC (clathrin-independent carriers/GPI-enriched early endosomal compartments) endocytic pathway. It strongly interacts with dynamin and inhibition of dynamin abolishes CLIC/GEEC endocytosis. GRAF2, GRAF3 and oligophrenin are likely to play similar roles during clathrin-independent endocytic events. GRAF1 mutations are linked to leukaemia. All members are composed of a N-terminal BAR-PH domain, followed by a RhoGAP domain, a proline rich region, and a C-terminal SH3 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 231 TMEGYLYVQEKRHFGTSWVKHYCTYQRDSKQITMVPFDQKSGGKGGEDESVILKSCTRRKTDSIEKRFCFDVEAVDRPGV 310
Cdd:cd01249     1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKLGTTEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                          90       100
                  ....*....|....*....|....*
gi 1370488740 311 ITMQALSEEDRRLWMEAMDGREPVY 335
Cdd:cd01249    81 LTLQALSEEDRKLWLEAMDGKEPIY 105

RhoGAP domain; GTPase activator proteins towards Rho/Rac/Cdc42-like small GTPases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 356 IIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVL-MDPKTASETEtdicaEWEIKTITSALKTYLRMLPGPLMMYQFQ 434
Cdd:pfam00620   3 IVRKCVEYLEKRGLDTEGIFRVSGSASRIKELREAFdRGPDVDLDLE-----EEDVHVVASLLKLFLRELPEPLLTFELY 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1370488740 435 RSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAK 477
Cdd:pfam00620  78 EEFIEAAKLPDEEERLEALRELLRKLPPANRDTLRYLLAHLNR 120

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 231 TMEGYLYVQEKrHFGTSWVKHYCTYQRDSkqitMVPFDQKSGGKGGEDESVI-LKSCTRR---KTDSIEKRFCFDVE--A 304
Cdd:pfam00169   2 VKEGWLLKKGG-GKKKSWKKRYFVLFDGS----LLYYKDDKSGKSKEPKGSIsLSGCEVVevvASDSPKRKFCFELRtgE 76

                          90       100
                  ....*....|....*....|....
gi 1370488740 305 VDRPGVITMQALSEEDRRLWMEAM 328
Cdd:pfam00169  77 RTGKRTYLLQAESEEERKDWIKAI 100

The Bin/Amphiphysin/Rvs (BAR) domain of Oligophrenin1-like Rho GTPase Activating Proteins; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. This subfamily is composed of Rho and Rac GTPase activating proteins (GAPs) with similarity to oligophrenin1 (OPHN1). Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, and a Rho GAP domain. Some members contain a C-terminal SH3 domain. Vertebrates harbor at least three Rho GAPs in this subfamily including OPHN1, GTPase Regulator Associated with Focal adhesion kinase (GRAF), GRAF2, and an uncharacterized protein called GAP10-like. OPHN1, GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. In addition, OPHN1 is active towards Rac. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domains of OPHN1 and GRAF directly interact with their Rho GAP domains and inhibit their activity. The autoinhibited proteins are able to bind membranes and tubulate liposomes, showing that the membrane-tubulation and GAP-inhibitory functions of the BAR domains can occur simultaneously.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  15 KDLSSAKRKFADSLNEFKFQCIGDAETDDEMCIARSLQEFATVLRNLEDERIRMIENASEVLITPLEKFRKEQIGAAKEA 94
Cdd:cd07602    33 KNLSKAQRSFAQTLQNFKFECIGETQTDDEIEIAESLKEFGRLIETVEDERDRMLENAEEQLIEPLEKFRKEQIGGAKEE 112

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  95 KKKYDKETEKYCGILEKHLNLSSKKKESQLQEADSQVDLVRQHFYEVSLEYVFKVQEVQERKMFEFVEPLLAFLQGLFTF 174
Cdd:cd07602   113 KKKFDKETEKFCSSLEKHLNLSTKKKENQLQEADAQLDMERRNFHQASLEYVFKLQEVQERKKFEFVETLLSFMYGWLTF 192

                         170
                  ....*....|....*
gi 1370488740 175 YHHGYELAKDFGDFK 189
Cdd:cd07602   193 YHQGHEVAKDFKPYL 207

The Bin/Amphiphysin/Rvs (BAR) domain of Rho GTPase activating protein 10-like; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. This group is composed of uncharacterized proteins called Rho GTPase activating protein (GAP) 10-like. GAP10-like may be a GAP with activity towards RhoA and Cdc42. Similar to GRAF and GRAF2, it contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domains of the related proteins GRAF and OPHN1, directly interact with their Rho GAP domains and inhibit theiractivity. The autoinhibited proteins are capable of binding membranes and tubulating liposomes, showing that the membrane-tubulation and GAP-inhibitory functions of the BAR domain can occur simultaneously.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  15 KDLSSAKRKFADSLNEFKFQCIGDAETDDEMCIARSLQEFATVLRNLEDERIRMIENASEVLITPLEKFRKEQIGAAKEA 94
Cdd:cd07634    33 RNLSMAVQKFSQSLQDFQFECIGDAETDDEISIAQSLKEFARLLIAVEEERRRLIQNANDVLIAPLEKFRKEQIGAAKDG 112

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  95 KKKYDKETEKYCGILEKHLNLSSKKKESQLQEADSQVDLVRQHFYEVSLEYVFKVQEVQERKMFEFVEPLLAFLQGLFTF 174
Cdd:cd07634   113 KKKFDKESEKYYSILEKHLNLSAKKKESHLQRADTQIDREHQNFYEASLEYVFKIQEVQEKKKFEFVEPLLAFLQGLFTF 192

                         170
                  ....*....|....*
gi 1370488740 175 YHHGYELAKDFGDFK 189
Cdd:cd07634   193 YHEGYELAQEFAPYK 207

BAR domain of APPL family; BAR_12 is the BAR coiled-coil domain at the N-terminus of APPL or adaptor protein containing PH domain, PTB domain, and leucine zipper motif proteins in higher eukaryotes. This BAR domain contains four helices whereas the other classical BAR domains contain only three helices. The first three helices form an antiparallel coiled-coil, while the fourth helix, is unique to APPL1. BAR domains take part in many varied biological processes such as fission of synaptic vesicles, endocytosis, regulation of the actin cytoskeleton, transcriptional repression, cell-cell fusion, apoptosis, secretory vesicle fusion, and tissue differentiation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  14 GKDLSSAKRKFADSLNEFKFQCIGDAETDDemciarSLQEFATVLRNLEDERIRMIENASEVLITPLEKFRKEQIGAAKE 93
Cdd:pfam16746  45 GKEYSAAQRLFANSLLDFKFEFIGDEETDE------SLKKFSQLLQEMENFHTILLDQAQRTIIKPLENFRKEDLKEVKE 118

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  94 AKKKYDKETEKYCGILEKHLNLSSKKKESQLQEADSQVDLVRQHFYEVSLEYVFKVQEVQERKMFEFVEPLLAFLQGLFT 173
Cdd:pfam16746 119 LKKKFDKASEKLDAALEKNAQLSKKKKPSELEEADNELAATRKCFHHASLDYVLQINELQERKKFEILEPLLSFMHAQFT 198

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|
gi 1370488740 174 FYHHGYELAKDFGDFKTQLTISIQNTRnrfEGTRSEVESL 213
Cdd:pfam16746 199 FFHQGYELFKDLEPFMKDLQAQLQQTR---EDTREEKEEL 235

GTPase Regulator Associated with Focal adhesion and related proteins Pleckstrin homology (PH) domain; This hierarchy contains GRAF family members: OPHN1/oligophrenin1, GRAF1 (also called ARHGAP26/Rho GTPase activating protein 26), GRAF2 (also called ARHGAP10/ARHGAP42), AK057372, and LOC129897, all of which are members of the APPL family. OPHN1 is a RhoGAP involved in X-linked mental retardation, epilepsy, rostral ventricular enlargement, and cerebellar hypoplasia. Affected individuals have morphological abnormalities of their brain with enlargement of the cerebral ventricles and cerebellar hypoplasia. OPHN1 negatively regulates RhoA, Cdc42, and Rac1 in neuronal and non-neuronal cells. GRAF1 sculpts the endocytic membranes of the CLIC/GEEC (clathrin-independent carriers/GPI-enriched early endosomal compartments) endocytic pathway. It strongly interacts with dynamin and inhibition of dynamin abolishes CLIC/GEEC endocytosis. GRAF2, GRAF3 and oligophrenin are likely to play similar roles during clathrin-independent endocytic events. GRAF1 mutations are linked to leukaemia. All members are composed of a N-terminal BAR-PH domain, followed by a RhoGAP domain, a proline rich region, and a C-terminal SH3 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 231 TMEGYLYVQEKRHFGTSWVKHYCTYQRDSKQITMVPFDQKSGGKGGEDESVILKSCTRRKTDSIEKRFCFDVEAVDRPGV 310
Cdd:cd01249     1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKLGTTEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                          90       100
                  ....*....|....*....|....*
gi 1370488740 311 ITMQALSEEDRRLWMEAMDGREPVY 335
Cdd:cd01249    81 LTLQALSEEDRKLWLEAMDGKEPIY 105

RhoGAP: GTPase-activator protein (GAP) for Rho-like GTPases; GAPs towards Rho/Rac/Cdc42-like small GTPases. Small GTPases (G proteins) cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when bound to GDP. The Rho family of small G proteins, which includes Cdc42Hs, activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. G proteins generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude. The RhoGAPs are one of the major classes of regulators of Rho G proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 356 IIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETEtdicaEWEIKTITSALKTYLRMLPGPLMMYQFQR 435
Cdd:cd00159     3 IIEKCIEYLEKNGLNTEGIFRVSGSASKIEELKKKFDRGEDIDDLE-----DYDVHDVASLLKLYLRELPEPLIPFELYD 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1370488740 436 SFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAK 477
Cdd:cd00159    78 EFIELAKIEDEEERIEALKELLKSLPPENRDLLKYLLKLLHK 119

RhoGAP_fRGD1: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of fungal RGD1-like proteins. Yeast Rgd1 is a GAP protein for Rho3 and Rho4 and plays a role in low-pH response. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 356 IIRKCIHAVETRGINEQGLYRIVGVNSRVQKL--------LSVLMDPKTASETEtdicaeweIKTITSALKTYLRMLPGP 427
Cdd:cd04398    19 IVYQCIQAIENFGLNLEGIYRLSGNVSRVNKLkelfdkdpLNVLLISPEDYESD--------IHSVASLLKLFFRELPEP 90

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1370488740 428 LMMYQFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAK-ENRYNQKRTSAS 489
Cdd:cd04398    91 LLTKALSREFIEAAKIEDESRRRDALHGLINDLPDANYATLRALMFHLARiKEHESVNRMSVN 153

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing proteins; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. This subfamily is composed of ACAPs (ArfGAP with Coiled-coil, ANK repeat and PH domain containing proteins), which are Arf GTPase activating proteins (GAPs) containing an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. Vertebrates contain at least three members, ACAP1, ACAP2, and ACAP3. ACAP1 and ACAP2 are Arf6-specific GAPs, involved in the regulation of endocytosis, phagocytosis, cell adhesion and migration, by mediating Arf6 signaling. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  14 GKDLSSAKRKFADSLNEFKFQCIGDAEtddemcIARSLQEFATVLRNLEDERIRMIENASEVLITPLEKFRKEQIGAAKE 93
Cdd:cd07603    32 GKTYVNANSLFVNSLNDLSDYFRDDSL------VQNCLNKFIQALQEMNNFHTILLDQAQRTVSTQLQNFVKEDIKKVKE 105

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  94 AKKKYDKETEKYCGILEKHLNLSsKKKESQLQEADSQVDLVRQHFYEVSLEYVFKVQEVQERKMFEFVEPLLAFLQGLFT 173
Cdd:cd07603   106 SKKHFEKISDDLDNALVKNAQAP-RSKPQEAEEATNILTATRSCFRHTALDYVLQINVLQAKKRHEILSTLLSYMHAQFT 184

                         170
                  ....*....|....*
gi 1370488740 174 FYHHGYELAKDFGDF 188
Cdd:cd07603   185 FFHQGYDLLEDLEPY 199

RhoGAP_chimaerin: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of chimaerins. Chimaerins are a family of phorbolester- and diacylglycerol-responsive GAPs specific for the Rho-like GTPase Rac. Chimaerins exist in two alternative splice forms that each contain a C-terminal GAP domain, and a central C1 domain which binds phorbol esters, inducing a conformational change that activates the protein; one splice form is lacking the N-terminal Src homology-2 (SH2) domain. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 356 IIRKCIHAVETRGINEQGLYRIVGVNSRVQkllsvlmDPKTASETE---TDICAEW--EIKTITSALKTYLRMLPGPLMM 430
Cdd:cd04372    19 VVDMCIREIEARGLQSEGLYRVSGFAEEIE-------DVKMAFDRDgekADISATVypDINVITGALKLYFRDLPIPVIT 91

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1370488740 431 YQFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAK 477
Cdd:cd04372    92 YDTYPKFIDAAKISNPDERLEAVHEALMLLPPAHYETLRYLMEHLKR 138

RhoGAP_MgcRacGAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in MgcRacGAP proteins. MgcRacGAP plays an important dual role in cytokinesis: i) it is part of centralspindlin-complex, together with the mitotic kinesin MKLP1, which is critical for the structure of the central spindle by promoting microtuble bundling. ii) after phosphorylation by aurora B MgcRacGAP becomes an effective regulator of RhoA and plays an important role in the assembly of the contractile ring and the initiation of cytokinesis. MgcRacGAP-like proteins contain a N-terminal C1-like domain, and a C-terminal RhoGAP domain. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 355 SIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETetdicAEWEIKTITSALKTYLRMLPGPLMMYQFQ 434
Cdd:cd04382    19 ALIVHCVNEIEARGLTEEGLYRVSGSEREVKALKEKFLRGKTVPNL-----SKVDIHVICGCLKDFLRSLKEPLITFALW 93

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1370488740 435 RSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAK 477
Cdd:cd04382    94 KEFMEAAEILDEDNSRAALYQAISELPQPNRDTLAFLILHLQR 136

RhoGAP_ARHGAP21: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of ArhGAP21-like proteins. ArhGAP21 is a multi-domain protein, containing RhoGAP, PH and PDZ domains, and is believed to play a role in the organization of the cell-cell junction complex. It has been shown to function as a GAP of Cdc42 and RhoA, and to interact with alpha-catenin and Arf6. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 356 IIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLmdpktaSETETDICAE---WE-IKTITSALKTYLRMLPGPLMMY 431
Cdd:cd04395    21 IVEVCCNIVEARGLETVGIYRVPGNNAAISALQEEL------NRGGFDIDLQdprWRdVNVVSSLLKSFFRKLPEPLFTN 94

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1370488740 432 QFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAK 477
Cdd:cd04395    95 ELYPDFIEANRIEDPVERLKELRRLIHSLPDHHYETLKHLIRHLKT 140

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 3; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. ACAP3 (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 3), also called centaurin beta-5, is presumed to be an Arf GTPase activating protein (GAP) based on its similarity to the Arf6-specific GAPs ACAP1 and ACAP2. The specific function of ACAP3 is still unknown. ACAP3 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  14 GKDLSSAKRKFADSLNEFKFQCIGDaetddEMcIARSLQEFATVLRNLEDERIRMIENASEVLITPLEKFRKEQIGAAKE 93
Cdd:cd07637    32 GKAYATTNKLFVSGIRDLSQQCKKD-----EM-ISECLDKFGDSLQEMVNYHMILFDQAQRSVRQQLHSFVKEDVRKFKE 105

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  94 AKKKYDKETEKYCGILEKHLNlSSKKKESQLQEADSQVDLVRQHFYEVSLEYVFKVQEVQERKMFEFVEPLLAFLQGLFT 173
Cdd:cd07637   106 TKKQFDKVREDLEIALVKNAQ-APRHKPHEVEEATSTLTITRKCFRHLALDYVLQINVLQAKKKFEILDSMLSFMHAQYT 184

                  ....*...
gi 1370488740 174 FYHHGYEL 181
Cdd:cd07637   185 FFQQGYSL 192

RhoGAP_CdGAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of CdGAP-like proteins; CdGAP contains an N-terminal RhoGAP domain and a C-terminal proline-rich region, and it is active on both Cdc42 and Rac1 but not RhoA. CdGAP is recruited to focal adhesions via the interaction with the scaffold protein actopaxin (alpha-parvin). Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 356 IIRKCIHAVETRGINEqGLYRIVGVNSRVQKLLSvlmdpKTASETETDICAEW---EIKTITSALKTYLRMLPGPLMMYQ 432
Cdd:cd04384    21 VLKSCTEFIEKHGIVD-GIYRLSGIASNIQRLRH-----EFDSEQIPDLTKDVyiqDIHSVSSLCKLYFRELPNPLLTYQ 94

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1370488740 433 FQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAK 477
Cdd:cd04384    95 LYEKFSEAVSAASDEERLEKIHDVIQQLPPPHYRTLEFLMRHLSR 139

RhoGAP_Bcr: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of Bcr (breakpoint cluster region protein)-like proteins. Bcr is a multidomain protein with a variety of enzymatic functions. It contains a RhoGAP and a Rho GEF domain, a Ser/Thr kinase domain, an N-terminal oligomerization domain, and a C-terminal PDZ binding domain, in addition to PH and C2 domains. Bcr is a negative regulator of: i) RacGTPase, via the Rho GAP domain, ii) the Ras-Raf-MEK-ERK pathway, via phosphorylation of the Ras binding protein AF-6, and iii) the Wnt signaling pathway through binding beta-catenin. Bcr can form a complex with beta-catenin and Tcf1. The Wnt signaling pathway is involved in cell proliferation, differentiation, and cell renewal. Bcr was discovered as a fusion partner of Abl. The Bcr-Abl fusion is characteristic for a large majority of chronic myelogenous leukemias (CML). Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 341 SQSEGTAQLDSIGFSIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLmdpKTASETETDICAEWEIKTITSALKTY 420
Cdd:cd04387     4 KISTVTKRERSKVPYIVRQCVEEVERRGMEEVGIYRISGVATDIQALKAAF---DTNNKDVSVMLSEMDVNAIAGTLKLY 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1370488740 421 LRMLPGPLMMYQFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAK 477
Cdd:cd04387    81 FRELPEPLFTDELYPNFAEGIALSDPVAKESCMLNLLLSLPDPNLVTFLFLLHHLKR 137

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 2; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. ACAP2 (ArfGAP with Coiled-coil, ANK repeat and PH domain containing protein 2), also called centaurin beta-2, is an Arf6-specific GTPase activating protein (GAP) which mediates Arf6 signaling. Arf6 is involved in the regulation of endocytosis, phagocytosis, cell adhesion and migration. ACAP2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  14 GKDLSSAKRKFADSLNEFKFQCIGDAetddemCIARSLQEFATVLRNLEDERIRMIENASEVLITPLEKFRKEQIGAAKE 93
Cdd:cd07638    32 GKAFCQANKQFMNGIRDLAQYSSKDA------VIETSLTKFSDTLQEMINYHTILFDQAQRSIKAQLQTFVKEDLRKFKD 105

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740  94 AKKKYDKETEKYCGILEKHLNLSsKKKESQLQEADSQVDLVRQHFYEVSLEYVFKVQEVQERKMFEFVEPLLAFLQGLFT 173
Cdd:cd07638   106 AKKQFDKVSEEKENALVKNAQVQ-RNKQHEVEEATNILTATRKCFRHIALDYVLQINVLQSKRRSEILKSMLSFMYAHLT 184

                         170
                  ....*....|....*
gi 1370488740 174 FYHHGYELAKDFGDF 188
Cdd:cd07638   185 FFHQGYDLFSELGPY 199

RhoGAP_GMIP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of GMIP (Gem interacting protein). GMIP plays important roles in neurite growth and axonal guidance, and interacts with Gem, a member of the RGK subfamily of the Ras small GTPase superfamily, through the N-terminal half of the protein. GMIP contains a C-terminal RhoGAP domain. GMIP inhibits RhoA function, but is inactive towards Rac1 and Cdc41. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 350 DSIGFsIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETetdicAEWEIKTITSALKTYLRMLPGPLM 429
Cdd:cd04408    14 EEVPF-VVVRCTAEIENRALGVQGIYRISGSKARVEKLCQAFENGRDLVDL-----SGHSPHDITSVLKHFLKELPEPVL 87

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1370488740 430 MYQFQRSFIKAAK--LENQESRVSE-------IHS---LVHRLPEKNRQMLQLLMNHLAK-ENRYNQKRTSA 488
Cdd:cd04408    88 PFQLYDDFIALAKelQRDSEKAAESpsiveniIRSlkeLLGRLPVSNYNTLRHLMAHLYRvAERFEDNKMSP 159

RhoGAP_SYD1: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in SYD-1_like proteins. Syd-1, first identified and best studied in C.elegans, has been shown to play an important role in neuronal development by specifying axonal properties. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 342 QSEGTAQLDSIgfsIIRKCIHAVETRGINEQGLYRIVGvNSRVQKLLSVLMDPKTASeteTDICAEW--EIKTITSALKT 419
Cdd:cd04379    10 EREGESRDVPI---VLQKCVQEIERRGLDVIGLYRLCG-SAAKKKELRDAFERNSAA---VELSEELypDINVITGVLKD 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 420 YLRMLPGPLMMYQFQRSFIKAA--KLENQ-ESRVSEIHSLVHRLPEKNRQMLQLLMNHLakenrynqkRTSASYH-HNIH 495
Cdd:cd04379    83 YLRELPEPLITPQLYEMVLEALavALPNDvQTNTHLTLSIIDCLPLSAKATLLLLLDHL---------SLVLSNSeRNKM 153

                         170       180       190
                  ....*....|....*....|....*....|....*
gi 1370488740 496 TCAYVSAISpvrqGNPVLLPKGIPFPGTLEPIDSP 530
Cdd:cd04379   154 TPQNLAVCF----GPVLMFCSQEFSRYGISPTSKM 184

RhoGAP_myosin_IXA: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in myosins IXA. Class IX myosins contain a characteristic head domain, a neck domain and a tail domain which contains a C6H2-zinc binding motif and a Rho-GAP domain. Class IX myosins are single-headed, processive myosins that are partly cytoplasmic, and partly associated with membranes and the actin cytoskeleton. Class IX myosins are implicated in the regulation of neuronal morphogenesis and function of sensory systems, like the inner ear. There are two major isoforms, myosin IXA and IXB with several splice variants, which are both expressed in developing neurons. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370488740 356 IIRKCIHAVETRGINEQGLYRIVGVNSRVQKLlsvlmdpKTASETETDICA--EWEIKTITSALKTYLRMLPGPLMMYQF 433
Cdd:cd04406    18 VVEKLINYIEMHGLYTEGIYRKSGSTNKIKEL-------RQGLDTDANSVNldDYNIHVIASVFKQWLRDLPNPLMTFEL 90

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1370488740 434 QRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLAK 477
Cdd:cd04406    91 YEEFLRAMGLQERRETVRGVYSVIDQLSRTHLNTLERLIFHLVR 134

ArfGAP with coiled-coil, ankyrin repeat and PH domains Pleckstrin homology (PH) domain; ACAP (also called centaurin beta) functions both as a Rab35 effector and as an Arf6-GTPase-activating protein (GAP) by which it controls actin remodeling and membrane trafficking. ACAP contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain, a phospholipid-binding domain, a PH domain, a GAP domain, and four ankyrin repeats. The AZAPs constitute a family of Arf GAPs that are characterized by an NH2-terminal pleckstrin homology (PH) domain and a central Arf GAP domain followed by two or more ankyrin repeats. On the basis of sequence and domain organization, the AZAP family is further subdivided into four subfamilies: 1) the ACAPs contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain (a phospholipid-binding domain that is thought to sense membrane curvature), a single PH domain followed by the GAP domain, and four ankyrin repeats; 2) the ASAPs also contain an NH2-terminal BAR domain, the tandem PH domain/GAP domain, three ankyrin repeats, two proline-rich regions, and a COOH-terminal Src homology 3 domain; 3) the AGAPs contain an NH2-terminal GTPase-like domain (GLD), a split PH domain, and the GAP domain followed by four ankyrin repeats; and 4) the ARAPs contain both an Arf GAP domain and a Rho GAP domain, as well as an NH2-terminal sterile-a motif (SAM), a proline-rich region, a GTPase-binding domain, and five PH domains. PMID 18003747 and 19055940 Centaurin can bind to phosphatidlyinositol (3,4,5)P3. 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.