The domain within your query sequence starts at position 383 and ends at position 564; the E-value for the RhoGAP domain shown below is 9.6e-60.

FEVPQVLQSCTAFIERYGIVDGIYRLSGVASNIQRLRHEFDSEHVPDLTKEPYVQDIHSV
GSLCKLYFRELPNPLLTYQLYEKFSDAVSAATDEERLIKIHDVIQQLPPPHYRTLEFLMR
HLSLLADYCSITNMHAKNLAIVWAPNLLRSKQIESACFSGTAAFMEVRIQSVVVEFILNH
VD

RhoGAP

GTPase-activator protein for Rho-like GTPases

• SMART accession number: SM00324
• Description: GTPase activator proteins towards Rho/Rac/Cdc42-like small GTPases. etter domain limits and outliers.
• Interpro abstract (IPR000198):

  Members of the Rho family of small G proteins transduce signals from plasma-membrane receptors and control cell adhesion, motility and shape by actin cytoskeleton formation. Like all other GTPases, Rho proteins act as molecular switches, with an active GTP-bound form and an inactive GDP-bound form. The active conformation is promoted by guanine-nucleotide exchange factors, and the inactive state by GTPase-activating proteins (GAPs) which stimulate the intrinsic GTPase activity of small G proteins. This entry is a Rho/Rac/Cdc42-like GAP domain, that is found in a wide variety of large, multi-functional proteins [ (PUBMED:9009196) ]. A number of structure are known for this family [ (PUBMED:9009196) (PUBMED:8962058) (PUBMED:9262406) ]. The domain is composed of seven alpha helices. This domain is also known as the breakpoint cluster region-homology (BH) domain.

• GO process: signal transduction (GO:0007165)

There are 47093 RhoGAP domains in 46979 proteins in SMART's nrdb database.

Cellular role (predicted cellular role)

Cellular role: signalling
Binding / catalysis: protein-binding, Rho-binding, GTPase activating

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Billuart P et al.
• Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation.
• Nature. 1998; 392: 923-6

Primary or nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which affected patients do not have any distinctive clinical or biochemical features in common apart from cognitive impairment. Although it is present in approximately 0.15-0.3% of males, most of the genetic defects associated with MRX, which may involve more than ten different genes, remain unknown. Here we report the characterization of a new gene on the long arm of the X-chromosome (position Xq12) and the identification in unrelated individuals of different mutations that are predicted to cause a loss of function. This gene is highly expressed in fetal brain and encodes a protein of relative molecular mass 91K, named oligophrenin-1, which contains a domain typical of a Rho-GTPase-activating protein (rhoGAP). By enhancing their GTPase activity, GAP proteins inactivate small Rho and Ras proteins, so inactivation of rhoGAP proteins might cause constitutive activation of their GTPase targets. Such activation is known to affect cell migration and outgrowth of axons and dendrites in vivo. Our results demonstrate an association between cognitive impairment and a defect in a signalling pathway that depends on a Ras-like GTPase.

• Barrett T et al.
• The structure of the GTPase-activating domain from p50rhoGAP.
• Nature. 1997; 385: 458-61

Members of the Rho family of small G proteins transduce signals from plasma-membrane receptors and control cell adhesion, motility and shape by actin cytoskeleton formation. They also activate other kinase cascades. Like all other GTPases, Rho proteins act as molecular switches, with an active GTP-bound form and an inactive GDP-bound form. The active conformation is promoted by guanine-nucleotide exchange factors, and the inactive state by GTPase-activating proteins (GAPs) which stimulate the intrinsic GTPase activity of small G proteins. Rho-specific GAP domains are found in a wide variety of large, multi-functional proteins. Here we report the crystal structure of an active 242-residue C-terminal fragment of human p50rhoGAP. The structure is an unusual arrangement of nine alpha-helices, the core of which includes a four-helix bundle. Residues conserved across the rhoGAP family are largely confined to one face of this bundle, which may be an interaction site for target G proteins. In particular, we propose that Arg 85 and Asn 194 are involved in binding G proteins and enhancing GTPase activity.

• Li R, Zhang B, Zheng Y
• Structural determinants required for the interaction between Rho GTPase and the GTPase-activating domain of p190.
• J Biol Chem. 1997; 272: 32830-5

The Rho family small GTP-binding proteins are subjected to regulation by Rho GTPase-activating proteins (GAPs) in the course of transmitting diverse intracellular signals. To understand the mechanism of GAP-catalyzed GTP hydrolysis of Rho GTPases, we have studied the interaction between RhoA and p190, the RasGAP binding phosphoprotein which has been implicated as a Rho-specific GAP, by delineating the structural determinants of RhoA and p190 GAP domain (p190GD) that are involved in their functional coupling. Besides the conserved residues Tyr34, Thr37, and Phe39 in the switch I region of RhoA which are required for p190GD interaction, chimeras made between RhoA and Cdc42, a close relative of RhoA with which p190GD interacts 50-fold less efficiently, revealed that residues outside the switch I and neighboring regions of RhoA, residues 85-122 in particular, contain the major p190GD-specifying determinant(s). Mutation of the unique Asp90 of RhoA in this region mostly abolished p190GD stimulation, whereas the corresponding reverse mutation of Cdc42 (S88D) was able to respond to p190GD-catalysis similarly as RhoA. Further kinetic analysis of these mutants provided evidence that Asp90 of RhoA contributes primarily to the specific binding interaction with p190GD. On the other hand, two charged residues of p190GD, Arg1283 and Lys1321, which are located in the putative G-protein binding helix pocket of GAP domain, were found to be involved in different aspects of interaction with RhoA. The R1283L mutant of p190GD lost GAP activity but retained the ability to bind to RhoA, while K1321A failed to stimulate and to bind to RhoA. These results indicate that residue Asp90 constitutes the second GAP-interactive site in RhoA which is mostly responsible for conferring p190GD-specificity, and suggest that the role of p190GD in the GTPase reaction of RhoA is in part to supply active site residue Arg1283 for efficient catalysis.

• Rittinger K, Walker PA, Eccleston JF, Smerdon SJ, Gamblin SJ
• Structure at 1.65 A of RhoA and its GTPase-activating protein in complex with a transition-state analogue.
• Nature. 1997; 389: 758-62

Small G proteins of the Rho family, which includes Rho, Rac and Cdc42Hs, regulate phosphorylation pathways that control a range of biological functions including cytoskeleton formation and cell proliferation. They operate as molecular switches, cycling between the biologically active GTP-bound form and the inactive GDP-bound state. Their rate of hydrolysis of GTP to GDP by virtue of their intrinsic GTPase activity is slow, but can be accelerated by up to 10(5)-fold through interaction with rhoGAP, a GTPase-activating protein that stimulates Rho-family proteins. As such, rhoGAP plays a crucial role in regulating Rho-mediated signalling pathways. Here we report the crystal structure of RhoA and rhoGAP complexed with the transition-state analogue GDP.AlF4- at 1.65 A resolution. There is a rotation of 20 degrees between the Rho and rhoGAP proteins in this complex when compared with the ground-state complex Cdc42Hs.GMPPNP/rhoGAP, in which Cdc42Hs is bound to the non-hydrolysable GTP analogue GMPPNP. Consequently, in the transition state complex but not in the ground state, the rhoGAP domain contributes a residue, Arg85(GAP) directly into the active site of the G protein. We propose that this residue acts to stabilize the transition state of the GTPase reaction. RhoGAP also appears to function by stabilizing several regions of RhoA that are important in signalling the hydrolysis of GTP.

• Rittinger K et al.
• Crystal structure of a small G protein in complex with the GTPase-activating protein rhoGAP.
• Nature. 1997; 388: 693-7

Small G proteins transduce signals from plasma-membrane receptors to control a wide range of cellular functions. These proteins are clustered into distinct families but all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of G proteins, which includes Cdc42Hs, activate effectors involved in the regulation of cytoskeleton formation, cell proliferation and the JNK signalling pathway. G proteins generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GTPase-activating proteins (GAPs) that enhance the rate of GTP hydrolysis by up to 10(5) times. We report here the crystal structure of Cdc42Hs, with the non-hydrolysable GTP analogue GMPPNP, in complex with the GAP domain of p50rhoGAP at 2.7A resolution. In the complex Cdc42Hs interacts, mainly through its switch I and II regions, with a shallow pocket on rhoGAP which is lined with conserved residues. Arg 85 of rhoGAP interacts with the P-loop of Cdc42Hs, but from biochemical data and by analogy with the G-protein subunit G(i alpha1), we propose that it adopts a different conformation during the catalytic cycle which enables it to stabilize the transition state of the GTP-hydrolysis reaction.

• Saras J, Franzen P, Aspenstrom P, Hellman U, Gonez LJ, Heldin CH
• A novel GTPase-activating protein for Rho interacts with a PDZ domain of the protein-tyrosine phosphatase PTPL1.
• J Biol Chem. 1997; 272: 24333-8

PTPL1 is an intracellular protein-tyrosine phosphatase that contains five PDZ domains. Here, we present the cloning of a novel 150-kDa protein, the four most C-terminal amino acid residues of which specifically interact with the fourth PDZ domain of PTPL1. The molecule contains a GTPase-activating protein (GAP) domain, a cysteine-rich, putative Zn2+- and diacylglycerol-binding domain, and a region of sequence homology to the product of the Caenorhabditis elegans gene ZK669.1a. The GAP domain is active on Rho, Rac, and Cdc42 in vitro but with a clear preference for Rho; we refer to the molecule as PTPL1-associated RhoGAP 1, PARG1. Rho is inactivated by GAPs, and protein-tyrosine phosphorylation has been implicated in Rho signaling. Therefore, a complex between PTPL1 and PARG1 may function as a powerful negative regulator of Rho signaling, acting both on Rho itself and on tyrosine phosphorylated components in the Rho signal transduction pathway.

• Musacchio A, Cantley LC, Harrison SC
• Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit.
• Proc Natl Acad Sci U S A. 1996; 93: 14373-8

Proteins such as the product of the break-point cluster region, chimaerin, and the Src homology 3-binding protein 3BP1, are GTPase activating proteins (GAPs) for members of the Rho subfamily of small GTP-binding proteins (G proteins or GTPases). A 200-residue region, named the breakpoint cluster region-homology (BH) domain, is responsible for the GAP activity. We describe here the crystal structure of the BH domain from the p85 subunit of phosphatidylinositol 3-kinase at 2.0 A resolution. The domain is composed of seven helices, having a previously unobserved arrangement. A core of four helices contains most residues that are conserved in the BH family. Their packing suggests the location of a G-protein binding site. This structure of a GAP-like domain for small GTP-binding proteins provides a framework for analyzing the function of this class of molecules.

• Boguski MS, McCormick F
• Proteins regulating Ras and its relatives.
• Nature. 1993; 366: 643-54

GTPases of the Ras superfamily regulate many aspects of cell growth, differentiation and action. Their functions depend on their ability to alternate between inactive and active forms, and on their cellular localization. Numerous proteins affecting the GTPase activity, nucleotide exchange rates and membrane localization of Ras superfamily members have now been identified. Many of these proteins are much larger and more complex than their targets, containing multiple domains capable of interacting with an intricate network of cellular enzymes and structures.

• Otsu M et al.
• Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase.
• Cell. 1991; 65: 91-104

Affinity-purified bovine brain phosphatidylinositol 3-kinase (PI3-kinase) contains two major proteins of 85 and 110 kd. Amino acid sequence analysis and cDNA cloning reveals two related 85 kd proteins (p85 alpha and p85 beta), which both contain one SH3 and two SH2 regions (src homology regions). When expressed, these 85 kd proteins bind to and are substrates for tyrosine-phosphorylated receptor kinases and the polyoma virus middle-T antigen/pp60c-src complex, but lack PI3-kinase activity. However, an antiserum raised against p85 beta immunoprecipitates PI3-kinase activity. The active PI3-kinase complex containing p85 alpha or p85 beta and the 110 kd protein binds to PDGF but not EGF receptors. p85 alpha and p85 beta may mediate specific PI3-kinase interactions with a subset of tyrosine kinases.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the RhoGAP domain.

Protein	Disease
Inositol polyphosphate 5-phosphatase OCRL-1 (Q01968) (SMART)	OMIM:309000: Lowe syndrome

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
5.86	map05212	Pancreatic cancer
5.05	map04670	Leukocyte transendothelial migration
5.05	map04510	Focal adhesion
4.44	map04070	Phosphatidylinositol signaling system
4.24	map05220	Chronic myeloid leukemia
3.84	map04360	Axon guidance
3.03	map05222	Small cell lung cancer
3.03	map05213	Endometrial cancer
3.03	map04370	VEGF signaling pathway
3.03	map04662	B cell receptor signaling pathway
3.03	map04630	Jak-STAT signaling pathway
3.03	map05214	Glioma
3.03	map04810	Regulation of actin cytoskeleton
3.03	map05223	Non-small cell lung cancer
3.03	map04664	Fc epsilon RI signaling pathway
3.03	map05210	Colorectal cancer
3.03	map04620	Toll-like receptor signaling pathway
3.03	map04210	Apoptosis
3.03	map04910	Insulin signaling pathway
3.03	map05215	Prostate cancer
3.03	map04012	ErbB signaling pathway
3.03	map04150	mTOR signaling pathway
3.03	map04660	T cell receptor signaling pathway
3.03	map05211	Renal cell carcinoma
3.03	map05221	Acute myeloid leukemia
3.03	map04930	Type II diabetes mellitus
3.03	map05218	Melanoma
3.03	map04650	Natural killer cell mediated cytotoxicity
3.03	map04914	Progesterone-mediated oocyte maturation
1.41	map00562	Inositol phosphate metabolism
0.20	map00750	Vitamin B6 metabolism
0.20	map00190	Oxidative phosphorylation

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with RhoGAP domain which could be assigned to a KEGG orthologous group, and not all proteins containing RhoGAP domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of RhoGAP domains in PDB

PDB code	Title
1am4	COMPLEX BETWEEN CDC42HS.GMPPNP AND P50 RHOGAP (H. SAPIENS)
1f7c	CRYSTAL STRUCTURE OF THE BH DOMAIN FROM GRAF, THE GTPASE REGULATOR ASSOCIATED WITH FOCAL ADHESION KINASE
1grn	CRYSTAL STRUCTURE OF THE CDC42/CDC42GAP/ALF3 COMPLEX.
1ow3	Crystal Structure of RhoA.GDP.MgF3-in Complex with RhoGAP
1pbw	STRUCTURE OF BCR-HOMOLOGY (BH) DOMAIN
1rgp	GTPASE-ACTIVATION DOMAIN FROM RHOGAP
1tx4	RHO/RHOGAP/GDP(DOT)ALF4 COMPLEX
1xa6	Crystal Structure of the Human Beta2-Chimaerin
2ee4	Solution structure of the RhoGAP domain from human Rho GTPase activating protein 5 variant
2ee5	Solution structure of the N-teruminus extended RhoGAP domain from human Rho GTPase activating protein 5 variant
2mbg	Rlip76 (gap-gbd)
2ngr	TRANSITION STATE COMPLEX FOR GTP HYDROLYSIS BY CDC42: COMPARISONS OF THE HIGH RESOLUTION STRUCTURES FOR CDC42 BOUND TO THE ACTIVE AND CATALYTICALLY COMPROMISED FORMS OF THE CDC42-GAP.
2osa	The Rho-GAP domain of human N-chimaerin
2ovj	The crystal structure of the human Rac GTPase activating protein 1 (RACGAP1) MgcRacGAP.
2qv2	A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway
2xs6	CRYSTAL STRUCTURE OF THE RHOGAP DOMAIN OF HUMAN PIK3R2
3byi	Crystal structure of human Rho GTPase activating protein 15 (ARHGAP15)
3cxl	Crystal structure of human chimerin 1 (CHN1)
3eap	Crystal structure of the RhoGAP domain of ARHGAP11A
3fk2	Crystal structure of the RhoGAP domain of human glucocorticoid receptor DNA-binding factor 1
3iug	Crystal structure of the RhoGAP domain of RICS
3kuq	Crystal structure of the DLC1 RhoGAP domain
3msx	Crystal structure of RhoA.GDP.MgF3 in complex with GAP domain of ArhGAP20
3qis	Recognition of the F&H motif by the Lowe Syndrome protein OCRL
3w6r	Crystal structure of the GAP domain of human MgcRacGAP
3wpq	3WPQ
3wps	3WPS
4u3k	4U3K
5c2j	5C2J
5c2k	5C2K
5c5s	5C5S
5hpy	5HPY
5irc	5IRC
5jcp	5JCP
5jd0	5JD0

Links (links to other resources describing this domain)

• INTERPRO: IPR000198
• PFAM: RhoGAP
• PROSITE: GDS_CDC24