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 208022687 364 MDGREPVYNSNKDSQS--EGTAQLDSIGFSIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETETDIC 441
Cdd:cd04374    1 MDGKEPVYHSPGRLQSevEGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKTSTPGDVDLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687 442 A-EWEIKTITSALKTYLRMLPGPLMMYQFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQ 520
Cdd:cd04374   81 NsEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|...
gi 208022687 521 NLMTVANLGVVFGPTLLRPQEETVAAIMDIKFQNIVIEILIEN 563
Cdd:cd04374  161 NLMTVSNLGVVFGPTLLRPQEETVAAIMDIKFQNIVVEILIEN 203

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase; GRAF, also called Rho GTPase activating protein 26 (ARHGAP26), Oligophrenin-1-like (OPHN1L) or GRAF1, is a GAP with activity towards RhoA and Cdc42 and is only weakly active towards Rac1. It influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase (FAK), which is a critical component of integrin signaling. It is essential for the major clathrin-independent endocytic pathway mediated by pleiomorphic membranes. GRAF contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 208022687 704 RKAKALYACKAEHDSELSFTAGTVFDNVHPSQEPGWLEGTLNGKTGLIPENYVEFL 759
Cdd:cd12064    1 RKAKALYACKAEHDSELSFTAGTVFDNVHPSQEPGWLEGTLNGKTGLIPENYVEFL 56

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 208022687 364 MDGREPVYNSNKDSQS--EGTAQLDSIGFSIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETETDIC 441
Cdd:cd04374    1 MDGKEPVYHSPGRLQSevEGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKTSTPGDVDLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687 442 A-EWEIKTITSALKTYLRMLPGPLMMYQFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQ 520
Cdd:cd04374   81 NsEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|...
gi 208022687 521 NLMTVANLGVVFGPTLLRPQEETVAAIMDIKFQNIVIEILIEN 563
Cdd:cd04374  161 NLMTVSNLGVVFGPTLLRPQEETVAAIMDIKFQNIVVEILIEN 203

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 208022687 267 TMEGYLYVQEKRHFGTSWVKHYCTYQRDSKQITMVPFDQKSGGKGGEDESVILKSCTRRKTDSIEKRFCFDVEAVDRPGV 346
Cdd:cd01249    1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKLGTTEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                         90       100
                 ....*....|....*....|....*
gi 208022687 347 ITMQALSEEDRRLWMEAMDGREPVY 371
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 208022687  392 IIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVL-MDPKTASETEtdicaEWEIKTITSALKTYLRMLPGPLMMYQFQ 470
Cdd:pfam00620   3 IVRKCVEYLEKRGLDTEGIFRVSGSASRIKELREAFdRGPDVDLDLE-----EEDVHVVASLLKLFLRELPEPLLTFELY 77

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687  471 RSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQNLMTVANLGVVFGPTLLRPQ 540
Cdd:pfam00620  78 EEFIEAAKLPDEEERLEALRELLRKLPPANRDTLRYLLAHLNRVAQNSDVNKMNAHNLAIVFGPTLLRPP 147

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 208022687   704 RKAKALYACKAEHDSELSFTAGTVFDNVHPSqEPGWLEGTLN-GKTGLIPENYVE 757
Cdd:smart00326   3 PQVRALYDYTAQDPDELSFKKGDIITVLEKS-DDGWWKGRLGrGKEGLFPSNYVE 56

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 208022687   267 TMEGYLYVQEKRHFGtSWVKHYCTYQRDskqiTMVPFDQKSGGKGGEDESVI-LKSCTRR---KTDSIEKRFCFDVEAVD 342
Cdd:smart00233   2 IKEGWLYKKSGGGKK-SWKKRYFVLFNS----TLLYYKSKKDKKSYKPKGSIdLSGCTVReapDPDSSKKPHCFEIKTSD 76

                           90       100
                   ....*....|....*....|..
gi 208022687   343 RpGVITMQALSEEDRRLWMEAM 364
Cdd:smart00233  77 R-KTLLLQAESEEEREKWVEAL 97

BAR domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687    20 ETLKSHEAELDKTNKFIKELIKDGKSLI---SALKNLSSAKRKFADSLNEFKFQCIGDAETDDEMCIARSLQEFATVLRN 96
Cdd:smart00721  27 EDFEELERRFDTTEAEIEKLQKDTKLYLqpnPAVRAKLASQKKLSKSLGEVYEGGDDGEGLGADSSYGKALDKLGEALKK 106

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687    97 LEDERIRMIENASEVLITPLEKFRKEQIGAAKEAKKK------YDKETEKycgiLEKHLNLSSKKKESQLQEADSQVDLV 170
Cdd:smart00721 107 LLQVEESLSQVKRTFILPLLNFLLGEFKEIKKARKKLerklldYDSARHK----LKKAKKSKEKKKDEKLAKAEEELRKA 182

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|
gi 208022687   171 RQHFYEVSLEYVFKVQEVQERKMFEFVEPLLAFLQGLFTFYHHGYELAKD 220
Cdd:smart00721 183 KQEFEESNAQLVEELPQLVASRVDFFVNCLQALIEAQLNFHRESYKLLQQ 232

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 208022687 364 MDGREPVYNSNKDSQS--EGTAQLDSIGFSIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETETDIC 441
Cdd:cd04374    1 MDGKEPVYHSPGRLQSevEGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKTSTPGDVDLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687 442 A-EWEIKTITSALKTYLRMLPGPLMMYQFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQ 520
Cdd:cd04374   81 NsEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|...
gi 208022687 521 NLMTVANLGVVFGPTLLRPQEETVAAIMDIKFQNIVIEILIEN 563
Cdd:cd04374  161 NLMTVSNLGVVFGPTLLRPQEETVAAIMDIKFQNIVVEILIEN 203

The Bin/Amphiphysin/Rvs (BAR) domain of GTPase Regulator Associated with Focal adhesion 2; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. GTPase Regulator Associated with Focal adhesion kinase 2 (GRAF2), also called Rho GTPase activating protein 10 (ARHGAP10) or PS-GAP, is a GAP with activity towards Cdc42 and RhoA which regulates caspase-activated p21-activated protein kinase-2 (PAK-2p34). GRAF2 interacts with PAK-2p34, leading to its stabilization and decrease of cell death. It is highly expressed in skeletal muscle and also interacts with PKNbeta, which is a target of Rho. GRAF2 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 domain of the related protein GRAF directly interacts with its Rho GAP domain and inhibits its activity. Autoinhibited GRAF is 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 208022687  19 RETLKSHEAELDKTNKFIKELIKDGKSLISALKNLSSAKRKFADSLNEFKFQCIGDAETDDEMCIARSLQEFATVLRNLE 98
Cdd:cd07635    1 RERIRAHEAELERTNRFIKELLKDGKNLIAATKSLSAAQRKFAHSLRDFKFEFIGDAETDDERCIDASLQEFSNFLKNLE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687  99 DERIRMIENASEVLITPLEKFRKEQIGAAKEAKKKYDKETEKYCGILEKHLNLSSKKKESQLQEADSQVDLVRQHFYEVS 178
Cdd:cd07635   81 EQREIMALNVTETLIKPLERFRKEQLGAVKEEKKKFDKETEKNYSLLEKHLNLSAKKKEPQLQEADVQVEQNRQHFYELS 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 208022687 179 LEYVFKVQEVQERKMFEFVEPLLAFLQGLFTFYHHGYELAKDFGDFK 225
Cdd:cd07635  161 LEYVCKLQEIQERKKFECVEPMLSFFQGVFTFYHQGYELAKDFNHYK 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 208022687    6 LEFSDCCLDSPHFRETLKSHEAELDKTNKFIKELIKDGKSLISALKNLSSAKRKFADSLNEFKFQCIGDAETDDemciar 85
Cdd:pfam16746   1 LEFEECLKDSPQFRSLLEEHEAELDELEKKLKKLLKLCKRMIEAGKEYSAAQRLFANSLLDFKFEFIGDEETDE------ 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687   86 SLQEFATVLRNLEDERIRMIENASEVLITPLEKFRKEQIGAAKEAKKKYDKETEKYCGILEKHLNLSSKKKESQLQEADS 165
Cdd:pfam16746  75 SLKKFSQLLQEMENFHTILLDQAQRTIIKPLENFRKEDLKEVKELKKKFDKASEKLDAALEKNAQLSKKKKPSELEEADN 154

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687  166 QVDLVRQHFYEVSLEYVFKVQEVQERKMFEFVEPLLAFLQGLFTFYHHGYELAKDFGDFKTQLTISIQNTRnrfEGTRSE 245
Cdd:pfam16746 155 ELAATRKCFHHASLDYVLQINELQERKKFEILEPLLSFMHAQFTFFHQGYELFKDLEPFMKDLQAQLQQTR---EDTREE 231

                  ....
gi 208022687  246 VESL 249
Cdd:pfam16746 232 KEEL 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 208022687 267 TMEGYLYVQEKRHFGTSWVKHYCTYQRDSKQITMVPFDQKSGGKGGEDESVILKSCTRRKTDSIEKRFCFDVEAVDRPGV 346
Cdd:cd01249    1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKLGTTEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                         90       100
                 ....*....|....*....|....*
gi 208022687 347 ITMQALSEEDRRLWMEAMDGREPVY 371
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 208022687 392 IIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETEtdicaEWEIKTITSALKTYLRMLPGPLMMYQFQR 471
Cdd:cd00159    3 IIEKCIEYLEKNGLNTEGIFRVSGSASKIEELKKKFDRGEDIDDLE-----DYDVHDVASLLKLYLRELPEPLIPFELYD 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687 472 SFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQNLMTVANLGVVFGPTLLRPQEETVAAIMDIK 551
Cdd:cd00159   78 EFIELAKIEDEEERIEALKELLKSLPPENRDLLKYLLKLLHKISQNSEVNKMTASNLAIVFAPTLLRPPDSDDELLEDIK 157

                        170
                 ....*....|..
gi 208022687 552 FQNIVIEILIEN 563
Cdd:cd00159  158 KLNEIVEFLIEN 169

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 208022687 392 IIRKCIHAVETRGINEQGLYRIVGVNSRVQkllsvlmDPKTASETE---TDICAEW--EIKTITSALKTYLRMLPGPLMM 466
Cdd:cd04372   19 VVDMCIREIEARGLQSEGLYRVSGFAEEIE-------DVKMAFDRDgekADISATVypDINVITGALKLYFRDLPIPVIT 91

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687 467 YQFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQNLMTVANLGVVFGPTLLRPQEETVAA 546
Cdd:cd04372   92 YDTYPKFIDAAKISNPDERLEAVHEALMLLPPAHYETLRYLMEHLKRVTLHEKDNKMNAENLGIVFGPTLMRPPEDSALT 171

                        170       180
                 ....*....|....*....|...
gi 208022687 547 IM-DIKFQNIVIEILIENHEKIF 568
Cdd:cd04372  172 TLnDMRYQILIVQLLITNEDVLF 194

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687  392 IIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVL-MDPKTASETEtdicaEWEIKTITSALKTYLRMLPGPLMMYQFQ 470
Cdd:pfam00620   3 IVRKCVEYLEKRGLDTEGIFRVSGSASRIKELREAFdRGPDVDLDLE-----EEDVHVVASLLKLFLRELPEPLLTFELY 77

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687  471 RSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQNLMTVANLGVVFGPTLLRPQ 540
Cdd:pfam00620  78 EEFIEAAKLPDEEERLEALRELLRKLPPANRDTLRYLLAHLNRVAQNSDVNKMNAHNLAIVFGPTLLRPP 147

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase; GRAF, also called Rho GTPase activating protein 26 (ARHGAP26), Oligophrenin-1-like (OPHN1L) or GRAF1, is a GAP with activity towards RhoA and Cdc42 and is only weakly active towards Rac1. It influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase (FAK), which is a critical component of integrin signaling. It is essential for the major clathrin-independent endocytic pathway mediated by pleiomorphic membranes. GRAF contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 208022687 704 RKAKALYACKAEHDSELSFTAGTVFDNVHPSQEPGWLEGTLNGKTGLIPENYVEFL 759
Cdd:cd12064    1 RKAKALYACKAEHDSELSFTAGTVFDNVHPSQEPGWLEGTLNGKTGLIPENYVEFL 56

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 208022687 392 IIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLmdpktaSETETDICAE---WE-IKTITSALKTYLRMLPGPLMMY 467
Cdd:cd04395   21 IVEVCCNIVEARGLETVGIYRVPGNNAAISALQEEL------NRGGFDIDLQdprWRdVNVVSSLLKSFFRKLPEPLFTN 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687 468 QFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQNLMTVANLGVVFGPTLLRPQEETVA-A 546
Cdd:cd04395   95 ELYPDFIEANRIEDPVERLKELRRLIHSLPDHHYETLKHLIRHLKTVADNSEVNKMEPRNLAIVFGPTLVRTSDDNMEtM 174

                        170       180
                 ....*....|....*....|..
gi 208022687 547 IMDIKFQNIVIEILIENHEKIF 568
Cdd:cd04395  175 VTHMPDQCKIVETLIQHYDWFF 196

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar proteins; This subfamily is composed of Rho GTPase activating proteins (GAPs) with similarity to GRAF. Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. Although vertebrates harbor four Rho GAPs in the GRAF subfamily including GRAF, GRAF2, GRAF3, and Oligophrenin-1 (OPHN1), only three are included in this model. OPHN1 contains the BAR, PH and GAP domains, but not the C-terminal SH3 domain. GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. GRAF influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase. GRAF2 regulates caspase-activated p21-activated protein kinase-2. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 208022687 705 KAKALYACKAEHDSELSFTAGTVFDNVHPSQEPGWLEGTLNGKTGLIPENYVEF 758
Cdd:cd11882    1 RARALYACKAEDESELSFEPGQIITNVQPSDEPGWLEGTLNGRTGLIPENYVEF 54

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 208022687 391 SIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETetdicAEWEIKTITSALKTYLRMLPGPLMMYQFQ 470
Cdd:cd04382   19 ALIVHCVNEIEARGLTEEGLYRVSGSEREVKALKEKFLRGKTVPNL-----SKVDIHVICGCLKDFLRSLKEPLITFALW 93

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687 471 RSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNhKQNLMTVANLGVVFGPTL---LRPQEETVAAI 547
Cdd:cd04382   94 KEFMEAAEILDEDNSRAALYQAISELPQPNRDTLAFLILHLQRVAQS-PECKMDINNLARVFGPTIvgySVPNPDPMTIL 172

                        170
                 ....*....|....*
gi 208022687 548 MDIKFQNIVIEILIE 562
Cdd:cd04382  173 QDTVRQPRVVERLLE 187

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 208022687 377 SQSEGTAQLDSIGFSIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLmdpKTASETETDICAEWEIKTITSALKTY 456
Cdd:cd04387    4 KISTVTKRERSKVPYIVRQCVEEVERRGMEEVGIYRISGVATDIQALKAAF---DTNNKDVSVMLSEMDVNAIAGTLKLY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687 457 LRMLPGPLMMYQFQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQNLMTVANLGVVFGPTL 536
Cdd:cd04387   81 FRELPEPLFTDELYPNFAEGIALSDPVAKESCMLNLLLSLPDPNLVTFLFLLHHLKRVAEREEVNKMSLHNLATVFGPTL 160

                 ....*...
gi 208022687 537 LRPQEETV 544
Cdd:cd04387  161 LRPSEKES 168

RhoGAP_PARG1: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of PARG1 (PTPL1-associated RhoGAP1). PARG1 was originally cloned as an interaction partner of PTPL1, an intracellular protein-tyrosine phosphatase. PARG1 interacts with Rap2, also a member of the Ras small GTPase superfamily whose exact function is unknown, and shows strong preference for Rho. 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 208022687 386 DSIGFsIIRKCIHAVETRGINEQGLYRIVGVNSRVQKLLSVLMDPKTASETetdicAEWEIKTITSALKTYLRMLPGPLM 465
Cdd:cd04409   14 DGIPF-IIKKCTSEIESRALCLKGIYRVNGAKSRVEKLCQAFENGKDLVEL-----SELSPHDISNVLKLYLRQLPEPLI 87

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687 466 MYQFQRSFIKAAK-----LENQESR-----------------VSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQNLM 523
Cdd:cd04409   88 LFRLYNEFIGLAKesqhvNETQEAKknsdkkwpnmctelnriLLKSKDLLRQLPAPNYNTLQFLIVHLHRVSEQAEENKM 167

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|..
gi 208022687 524 TVANLGVVFGPTLLRPQ----EETVAAIMDIKFQNIVIEILI 561
Cdd:cd04409  168 SASNLGIIFGPTLIRPRptdaTVSLSSLVDYPHQARLVELLI 209

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 208022687 392 IIRKCIHAVETRGINEqGLYRIVGVNSRVQKLLSvlmdpKTASETETDICAEW---EIKTITSALKTYLRMLPGPLMMYQ 468
Cdd:cd04384   21 VLKSCTEFIEKHGIVD-GIYRLSGIASNIQRLRH-----EFDSEQIPDLTKDVyiqDIHSVSSLCKLYFRELPNPLLTYQ 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208022687 469 FQRSFIKAAKLENQESRVSEIHSLVHRLPEKNRQMLQLLMNHLANVANNHKQNLMTVANLGVVFGPTLLRPQE------E 542
Cdd:cd04384   95 LYEKFSEAVSAASDEERLEKIHDVIQQLPPPHYRTLEFLMRHLSRLAKYCSITNMHAKNLAIVWAPNLLRSKQiesacfS 174

                        170       180
                 ....*....|....*....|.
gi 208022687 543 TVAAIMDIKFQNIVIEILIEN 563
Cdd:cd04384  175 GTAAFMEVRIQSVVVEFILNH 195