Beta-spectrin pleckstrin homology (PH) domain; ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with RhoGAP domain. The ARHGAP members here all have a PH domain upstream of their C-terminal RhoGAP domain. Some have additional N-terminal SH3 and WW domains. The members here include: ARHGAP9, ARHGAP12, ARHGAP15, and ARHGAP27. ARHGAP27 and ARHGAP12 shared the common-domain structure, consisting of SH3, WW, PH, and RhoGAP domains. The PH domain of ArhGAP9 employs a non-canonical phosphoinositide binding mechanism, a variation of the spectrin- Ins(4,5)P2-binding mode, that gives rise to a unique PI binding profile, namely a preference for both PI(4,5)P2 and the PI 3-kinase products PI(3,4,5)P3 and PI(3,4)P2. This lipid binding mechanism is also employed by the PH domain of Tiam1 and Slm1. 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 568967396 236 ERSGLLNMTKIAQGGRKLRKNWGPAWVVLTGSSLVFYRErpPQSAslQGWARAGSRPESSVDLRGAALASGRQLSSRRNV 315
Cdd:cd13233    1 EKQGLLNKTKIAENGKKLRKNWSTSWVVLTSSHLLFYKD--AKSA--AKSGNPYSKPESSVDLRGASIEWAKEKSSRKNV 76

                         90       100       110
                 ....*....|....*....|....*....|....
gi 568967396 316 LHIRTVPGHEFLLQSDEETELRDWHRALRTVIER 349
Cdd:cd13233   77 FQISTVTGTEFLLQSDNDTEIREWFDAIKAVIQR 110

Beta-spectrin pleckstrin homology (PH) domain; ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with RhoGAP domain. The ARHGAP members here all have a PH domain upstream of their C-terminal RhoGAP domain. Some have additional N-terminal SH3 and WW domains. The members here include: ARHGAP9, ARHGAP12, ARHGAP15, and ARHGAP27. ARHGAP27 and ARHGAP12 shared the common-domain structure, consisting of SH3, WW, PH, and RhoGAP domains. The PH domain of ArhGAP9 employs a non-canonical phosphoinositide binding mechanism, a variation of the spectrin- Ins(4,5)P2-binding mode, that gives rise to a unique PI binding profile, namely a preference for both PI(4,5)P2 and the PI 3-kinase products PI(3,4,5)P3 and PI(3,4)P2. This lipid binding mechanism is also employed by the PH domain of Tiam1 and Slm1. 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 568967396 236 ERSGLLNMTKIAQGGRKLRKNWGPAWVVLTGSSLVFYRErpPQSAslQGWARAGSRPESSVDLRGAALASGRQLSSRRNV 315
Cdd:cd13233    1 EKQGLLNKTKIAENGKKLRKNWSTSWVVLTSSHLLFYKD--AKSA--AKSGNPYSKPESSVDLRGASIEWAKEKSSRKNV 76

                         90       100       110
                 ....*....|....*....|....*....|....
gi 568967396 316 LHIRTVPGHEFLLQSDEETELRDWHRALRTVIER 349
Cdd:cd13233   77 FQISTVTGTEFLLQSDNDTEIREWFDAIKAVIQR 110

GTPase-activator protein for Rho-like GTPases; GTPase activator proteins towards Rho/Rac/Cdc42-like small GTPases. etter domain limits and outliers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568967396   451 DTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRflvdreravtsdgrymfpEQAGQEGKLDLDSAEWDdIHVVTG 530
Cdd:smart00324   1 KPIPIIVEKCIEYLEKRGLDTEGIYRVSGSKSRVKELR------------------DAFDSGPDPDLDLSEYD-VHDVAG 61

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 568967396   531 ALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHL 590
Cdd:smart00324  62 LLKLFLRELPEPLITYELYEEFIEAAKLEDETERLRALRELLSLLPPANRATLRYLLAHL 121

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 568967396   250 GRKLRKNWGPAWVVLTGSSLVFYRERPpqsaslqgwARAGSRPESSVDLRGA--ALASGRQLSSRRNVLHIRTVPGHEFL 327
Cdd:smart00233  11 SGGGKKSWKKRYFVLFNSTLLYYKSKK---------DKKSYKPKGSIDLSGCtvREAPDPDSSKKPHCFEIKTSDRKTLL 81

                           90       100
                   ....*....|....*....|
gi 568967396   328 LQSDEETELRDWHRALRTVI 347
Cdd:smart00233  82 LQAESEEEREKWVEALRKAI 101

Variant SH3 domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 568967396   29 ALYPFTYTGADgrQVSLAEGDRFLLLRKTNSDWWLARRLGappssRPIFVPAAY 82
Cdd:pfam14604   1 ALYPYEPKDDD--ELSLQRGDVITVIEESEDGWWEGINTG-----RTGLVPANY 47

Beta-spectrin pleckstrin homology (PH) domain; ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with RhoGAP domain. The ARHGAP members here all have a PH domain upstream of their C-terminal RhoGAP domain. Some have additional N-terminal SH3 and WW domains. The members here include: ARHGAP9, ARHGAP12, ARHGAP15, and ARHGAP27. ARHGAP27 and ARHGAP12 shared the common-domain structure, consisting of SH3, WW, PH, and RhoGAP domains. The PH domain of ArhGAP9 employs a non-canonical phosphoinositide binding mechanism, a variation of the spectrin- Ins(4,5)P2-binding mode, that gives rise to a unique PI binding profile, namely a preference for both PI(4,5)P2 and the PI 3-kinase products PI(3,4,5)P3 and PI(3,4)P2. This lipid binding mechanism is also employed by the PH domain of Tiam1 and Slm1. 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 568967396 236 ERSGLLNMTKIAQGGRKLRKNWGPAWVVLTGSSLVFYRErpPQSAslQGWARAGSRPESSVDLRGAALASGRQLSSRRNV 315
Cdd:cd13233    1 EKQGLLNKTKIAENGKKLRKNWSTSWVVLTSSHLLFYKD--AKSA--AKSGNPYSKPESSVDLRGASIEWAKEKSSRKNV 76

                         90       100       110
                 ....*....|....*....|....*....|....
gi 568967396 316 LHIRTVPGHEFLLQSDEETELRDWHRALRTVIER 349
Cdd:cd13233   77 FQISTVTGTEFLLQSDNDTEIREWFDAIKAVIQR 110

GTPase-activator protein for Rho-like GTPases; GTPase activator proteins towards Rho/Rac/Cdc42-like small GTPases. etter domain limits and outliers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568967396   451 DTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRflvdreravtsdgrymfpEQAGQEGKLDLDSAEWDdIHVVTG 530
Cdd:smart00324   1 KPIPIIVEKCIEYLEKRGLDTEGIYRVSGSKSRVKELR------------------DAFDSGPDPDLDLSEYD-VHDVAG 61

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 568967396   531 ALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHL 590
Cdd:smart00324  62 LLKLFLRELPEPLITYELYEEFIEAAKLEDETERLRALRELLSLLPPANRATLRYLLAHL 121

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 568967396 454 PSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFLVDRERavtsdgrymfpeqagqegklDLDSAEWDDIHVVTGALK 533
Cdd:cd00159    1 PLIIEKCIEYLEKNGLNTEGIFRVSGSASKIEELKKKFDRGE--------------------DIDDLEDYDVHDVASLLK 60

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 568967396 534 LFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHLCR 592
Cdd:cd00159   61 LYLRELPEPLIPFELYDEFIELAKIEDEEERIEALKELLKSLPPENRDLLKYLLKLLHK 119

Src Homology 3 domain of Rho GTPase-activating protein 9 and similar proteins; Rho GTPase-activating proteins (RhoGAPs or ARHGAPs) bind to Rho proteins and enhance the hydrolysis rates of bound GTP. ARHGAP9 functions as a GAP for Rac and Cdc42, but not for RhoA. It negatively regulates cell migration and adhesion. It also acts as a docking protein for the MAP kinases Erk2 and p38alpha, and may facilitate cross-talk between the Rho GTPase and MAPK pathways to control actin remodeling. It contains SH3, WW, Pleckstin homology (PH), and RhoGAP domains. 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 568967396  26 QLCALYPFTYTGADGRQVSLAEGDRFLLLRKTNSDWWLARRLGAPPSSRPIFVPAAY 82
Cdd:cd12143    1 QLCALYAYQYTGADGRQVSIAEGERFLLLRKTNSDWWQVRRLEAPSTSRPLFVPATY 57

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 568967396 438 FGCQLESLCQREGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFLVDReravtsDGRymfpeqagqegKLDL 517
Cdd:cd04372    1 YGCDLTTLVKAHNTQRPMVVDMCIREIEARGLQSEGLYRVSGFAEEIEDVKMAFDR------DGE-----------KADI 63

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 568967396 518 DSAEWDDIHVVTGALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHLCR 592
Cdd:cd04372   64 SATVYPDINVITGALKLYFRDLPIPVITYDTYPKFIDAAKISNPDERLEAVHEALMLLPPAHYETLRYLMEHLKR 138

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 568967396 438 FGCQLESLCQREGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFLVD-RERAVTSDGRYMfpeqagqegkld 516
Cdd:cd04387    1 FGVKISTVTKRERSKVPYIVRQCVEEVERRGMEEVGIYRISGVATDIQALKAAFDtNNKDVSVMLSEM------------ 68

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 568967396 517 ldsaewdDIHVVTGALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHLCR 592
Cdd:cd04387   69 -------DVNAIAGTLKLYFRELPEPLFTDELYPNFAEGIALSDPVAKESCMLNLLLSLPDPNLVTFLFLLHHLKR 137

RhoGAP_myosin_IX: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in class IX myosins. Class IX myosins contain a characteristic head domain, a neck domain, a tail domain which contains a C6H2-zinc binding motif and a RhoGAP 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 568967396 438 FGCQLESLCQrEGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFLVDReravtsdgrymfpeqagqegklDL 517
Cdd:cd04377    1 FGVSLSSLTS-EDRSVPLVLEKLLEHIEMHGLYTEGIYRKSGSANKIKELRQGLDT----------------------DP 57

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 568967396 518 DSAEWDD--IHVVTGALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHLCR 592
Cdd:cd04377   58 DSVNLEDypIHVITSVLKQWLRELPEPLMTFELYENFLRAMELEEKQERVRALYSVLEQLPRANLNTLERLIFHLVR 134

RhoGAP_nadrin: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of Nadrin-like proteins. Nadrin, also named Rich-1, has been shown to be involved in the regulation of Ca2+-dependent exocytosis in neurons and recently has been implicated in tight junction maintenance in mammalian epithelium. 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 568967396 436 QVFGCQLESLCQREGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFLVDreravtsdgrymfpeqAGQEgKL 515
Cdd:cd04386    3 PVFGTPLEEHLKRTGREIALPIEACVMCLLETGMNEEGLFRVGGGASKLKRLKAALD----------------AGTF-SL 65

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 568967396 516 DLDSaEWDDIHVVTGALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHLC 591
Cdd:cd04386   66 PLDE-FYSDPHAVASALKSYLRELPDPLLTYNLYEDWVQAANKPDEDERLQAIWRILNKLPRENRDNLRYLIKFLS 140

RhoGAP-p50rhoGAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of p50RhoGAP-like proteins; p50RhoGAP, also known as RhoGAP-1, contains a C-terminal RhoGAP domain and an N-terminal Sec14 domain which binds phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). It is ubiquitously expressed and preferentially active on Cdc42. This subgroup also contains closely related ARHGAP8. 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 568967396 436 QVFGCQLESLCQR--EGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFLVDReravtsdgrymfpeqagqeg 513
Cdd:cd04404    4 QQFGVSLQFLKEKnpEQEPIPPVVRETVEYLQAHALTTEGIFRRSANTQVVKEVQQKYNM-------------------- 63

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 568967396 514 KLDLDSAEWDDIHVVTGALKLFFRELPQPLVPALLLPDFRDALELSEPEQcLSKIQKLIDSLPRPNHDTLKYILEHLCR 592
Cdd:cd04404   64 GEPVDFDQYEDVHLPAVILKTFLRELPEPLLTFDLYDDIVGFLNVDKEER-VERVKQLLQTLPEENYQVLKYLIKFLVQ 141

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 568967396 455 SFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKL-RFLVDRERAvtsdgrymfpeqagQEGKLDLDSAEWDdIHVVTGALK 533
Cdd:cd04374   30 KFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLlSLGLDPKTS--------------TPGDVDLDNSEWE-IKTITSALK 94

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 568967396 534 LFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHLCRSGGLSN 598
Cdd:cd04374   95 TYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSK 159

RhoGAP_myosin_IXB: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in myosins IXB. 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 568967396 438 FGCQLESLCQrEGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFLVdreravtsdgrymfpeQAGQEG-KLd 516
Cdd:cd04407    1 FGVRVGSLTS-NKTSVPIVLEKLLEHVEMHGLYTEGIYRKSGSANRMKELHQLL----------------QADPENvKL- 62

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 568967396 517 ldsaEWDDIHVVTGALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHLCR 592
Cdd:cd04407   63 ----ENYPIHAITGLLKQWLRELPEPLMTFAQYNDFLRAVELPEKQEQLQAIYRVLEQLPTANHNTLERLIFHLVK 134

RhoGAP_ARHGAP18: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of ArhGAP18-like proteins. The function of ArhGAP18 is unknown. 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 568967396 437 VFGCQLESLCQR-----EGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGnlaVVQKLRFLVDRERAVTSDGRYMFpEQAGQ 511
Cdd:cd04391    1 LFGVPLSTLLERdqkkvPGSKVPLIFQKLINKLEERGLETEGILRIPG---SAQRVKFLCQELEAKFYEGTFLW-DQVKQ 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 568967396 512 egkldldsaewddiHVVTGALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHL 590
Cdd:cd04391   77 --------------HDAASLLKLFIRELPQPLLTVEYLPAFYSVQGLPSKKDQLQALNLLVLLLPEANRDTLKALLEFL 141

RhoGAP_FAM13A1a: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of FAM13A1, isoform a-like proteins. The function of FAM13A1a is unknown. 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 up several orders of magnitude.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568967396 436 QVFGCQLESLcQREG---DTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFlvdreravtsdgRYmfpeqagqE 512
Cdd:cd04393    1 KVFGVPLQEL-QQAGqpeNGVPAVVRHIVEYLEQHGLEQEGLFRVNGNAETVEWLRQ------------RL--------D 59

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568967396 513 GKLDLDSAEWDDIHVVTGALKLFFRELPQPLVPALLLPDF-RDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHLC 591
Cdd:cd04393   60 SGEEVDLSKEADVCSAASLLRLFLQELPEGLIPASLQIRLmQLYQDYNGEDEFGRKLRDLLQQLPPVNYSLLKFLCHFLS 139

                 .
gi 568967396 592 R 592
Cdd:cd04393  140 N 140

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 568967396 438 FGCQLESLCQREGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRflvdreravtsdgrymfpeQAGQEGKLDL 517
Cdd:cd04409    1 FGADFAQVAKKSPDGIPFIIKKCTSEIESRALCLKGIYRVNGAKSRVEKLC-------------------QAFENGKDLV 61

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568967396 518 DSAEWDDiHVVTGALKLFFRELPQPLVPALLLPDF-------------RDALELSEPEQ---------CLSKIQKLIDSL 575
Cdd:cd04409   62 ELSELSP-HDISNVLKLYLRQLPEPLILFRLYNEFiglakesqhvnetQEAKKNSDKKWpnmctelnrILLKSKDLLRQL 140

                        170
                 ....*....|....*..
gi 568967396 576 PRPNHDTLKYILEHLCR 592
Cdd:cd04409  141 PAPNYNTLQFLIVHLHR 157

RhoGAP_srGAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in srGAPs. srGAPs are components of the intracellular part of Slit-Robo signalling pathway that is important for axon guidance and cell migration. srGAPs contain an N-terminal FCH domain, a central RhoGAP domain and a C-terminal SH3 domain; this SH3 domain interacts with the intracellular proline-rich-tail of the Roundabout receptor (Robo). This interaction with Robo then activates the rhoGAP domain which in turn inhibits Cdc42 activity. 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 568967396 438 FGCQLESLCQREGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFLVDReravtsdgrymfpeqaGQEGKLDL 517
Cdd:cd04383    3 FNGSLEEYIQDSGQAIPLVVESCIRFINLYGLQHQGIFRVSGSQVEVNDIKNAFER----------------GEDPLADD 66

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 568967396 518 DSAEwdDIHVVTGALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYI---LEHLC 591
Cdd:cd04383   67 QNDH--DINSVAGVLKLYFRGLENPLFPKERFEDLMSCVKLENPTERVHQIREILSTLPRSVIIVMRYLfafLNHLS 141

ARHGAP21 and related proteins pleckstrin homology (PH) domain; ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with a RhoGAP domain. These proteins functions as a GTPase-activating protein (GAP) for RHOA and CDC42. ARHGAP21 controls the Arp2/3 complex and F-actin dynamics at the Golgi complex by regulating the activity of the small GTPase Cdc42. It is recruited to the Golgi by to GTPase, ARF1, through its PH domain and its helical motif. It is also required for CTNNA1 recruitment to adherens junctions. ARHGAP21 and it related proteins all contains a PH domain and a RhoGAP domain. Some of the members have additional N-terminal domains including PDZ, SH3, and SPEC. The ARHGAP21 PH domain interacts with the GTPbound forms of both ARF1 and ARF6 ARF-binding domain/ArfBD. The members here include: ARHGAP15, ARHGAP21, and ARHGAP23. 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 568967396 236 ERSGLLNMTKIA--QGGRKLRKNWGPAWVVLTGSSLVFYRERPPQSASLQGWARAGSRpessVDLRGAALASGRQLSSRR 313
Cdd:cd01253    1 AREGWLHYKQIVtdKGKRVSDRSWKQAWAVLRGHSLYLYKDKREQTPALSIELGSEQR----ISIRGCIVDIAYSYTKRK 76

                         90       100       110
                 ....*....|....*....|....*....|.
gi 568967396 314 NVLHIRTVPGHEFLLQSDEETELRDWHRALR 344
Cdd:cd01253   77 HVFRLTTSDFSEYLFQAEDRDDMLGWIKAIQ 107

RhoGAP_ARHGAP20: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of ArhGAP20-like proteins. ArhGAP20, also known as KIAA1391 and RA-RhoGAP, contains a RhoGAP, a RA, and a PH domain, and ANXL repeats. ArhGAP20 is activated by Rap1 and induces inactivation of Rho, which in turn leads to neurite outgrowth. 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 568967396 438 FGCQLESLCqrEGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRflvdreravtsdgrymfpEQAGQEGKLDL 517
Cdd:cd04402    2 FGQPLSNIC--EDDNLPKPILDMLSLLYQKGPSTEGIFRRSANAKACKELK------------------EKLNSGVEVDL 61

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568967396 518 DSaewDDIHVVTGALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYIL 587
Cdd:cd04402   62 KA---EPVLLLASVLKDFLRNIPGSLLSSDLYEEWMSALDQENEEEKIAELQRLLDKLPRPNVLLLKHLI 128

RhoGAP_KIAA1688: GTPase-activator protein (GAP) domain for Rho-like GTPases found in KIAA1688-like proteins; KIAA1688 is a protein of unknown function that contains a RhoGAP domain and a myosin tail homology 4 (MyTH4) 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 568967396 438 FGCQLESLCQREGDTVPSF------VRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFLVDReravtsdGRYmfpeqagq 511
Cdd:cd04389    1 FGSSLEEIMDRQKEKYPELklpwilTFLSEKVLALGGFQTEGIFRVPGDIDEVNELKLRVDQ-------WDY-------- 65

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568967396 512 egkldlDSAEWDDIHVVTGALKLFFRELPQPLVPALLlpdFRDALELSE-PEqclsKIQKLIDSLPRPNHDTLKYILEHL 590
Cdd:cd04389   66 ------PLSGLEDPHVPASLLKLWLRELEEPLIPDAL---YQQCISASEdPD----KAVEIVQKLPIINRLVLCYLINFL 132

RhoGAP_DLC1: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of DLC1-like proteins. DLC1 shows in vitro GAP activity towards RhoA and CDC42. Beside its C-terminal GAP domain, DLC1 also contains a SAM (sterile alpha motif) and a START (StAR-related lipid transfer action) domain. DLC1 has tumor suppressor activity in cell culture. 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 568967396 437 VFGCQLESLCQREGDTVPSFVRLCVEAVDKKGLDVDGIYRVSGNLAVVQKLRFLVdreravtsdgrymfpEQAGQEGKLD 516
Cdd:cd04375    4 VFGVPLLVNLQRTGQPLPRSIQQAMRWLRNNALDQVGLFRKSGVKSRIQKLRSMI---------------ESSTDNVNYD 68

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 568967396 517 LDSAewddiHVVTGALKLFFRELPQPLVPALLLPDFRDALELSEPEQCLSKIQKLIDSLPRPNHDTLKYILEHL 590
Cdd:cd04375   69 GQQA-----YDVADMLKQYFRDLPEPLLTNKLSETFIAIFQYVPKEQRLEAVQCAILLLPDENREVLQTLLYFL 137