PROSITE documentation PDOC00438
Ras GTPase-activating proteins signature and profile


Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyze GTP to GDP [1]. This intrinsic GTPase activity of ras is stimulated by a family of proteins collectively known as 'GAP' or GTPase-activating proteins [2,3]. As it is the GTP bound form of ras which is active, these proteins are said to be down-regulators of ras. Proteins known to possess such activity are listed below:

  • Mammalian GAP (p120GAP). GAP can down-regulate wild-type ras, but fails to do so with oncogenic, mutated ras.
  • IRA1 and IRA2, the functional equivalents of GAP in yeast. They regulate the RAS-cyclic AMP pathway, controlling cell growth.
  • sar1, the fission yeast protein that regulates ras1 in that organism.
  • BUD2/CLA2, a yeast protein that activates BUD1/RSR1 and which participates in the regulation of bud-site selection [4].
  • Neurofibromin (gene NF1) [5]. In Man, NF1 is associated with type 1 neurofibromatosis, one of the most frequently inherited genetic diseases characterized, in part, by multiple neural tumors. NF1 has been shown genetically and biochemically to interact with and stimulate the GTPase activity of h-ras.
  • Drosophila Gap1 [6], which acts as a negative regulator of signalling by the Sevenless receptor tyrosine kinase involved in eye development.
  • Mammalian Gap1m [7], which is related to the drosophila Gap1 protein.
  • Human IQGAP1 [8], a sar1-related protein that also contains putative calmodulin binding sites.

All the above proteins are quite large (from 765 residues for sar1 to 3079 residues for IRA2) but share only a limited (about 250 residues) region of sequence similarity, referred to as the 'catalytic domain' or rasGAP domain. The most conserved region within this domain contains a 15 residue motif which seems to be characteristic of this family of proteins [2]. A more sensitive detection of the rasGAP domain is available through the use of a profile which spans the whole conserved region.


There are distinctly different GAPs for the rap and rho/rac subfamilies of ras-like proteins (reviewed in reference [9]) that do not share sequence similarity with ras GAPs.

Last update:

December 2004 / Pattern and text revised.


Technical section

PROSITE methods (with tools and information) covered by this documentation:

RAS_GTPASE_ACTIV_2, PS50018; Ras GTPase-activating proteins profile  (MATRIX)

RAS_GTPASE_ACTIV_1, PS00509; Ras GTPase-activating proteins domain signature  (PATTERN)


1AuthorsBourne H.R. Sanders D.A. McCormick F.
TitleThe GTPase superfamily: conserved structure and molecular mechanism.
SourceNature 349:117-127(1991).
PubMed ID1898771

2AuthorsWang Y. Boguski M.S. Riggs M. Rodgers L. Wigler M.
Titlesar1, a gene from Schizosaccharomyces pombe encoding a protein that regulates ras1.
SourceCell Regul. 2:453-465(1991).
PubMed ID1883874

3AuthorsMaruta H. Burgess A.W.
TitleRegulation of the Ras signalling network.
SourceBioEssays 16:489-496(1994).
PubMed ID7945277

4AuthorsPark H.O. Chant J. Herskowitz I.
TitleBUD2 encodes a GTPase-activating protein for Bud1/Rsr1 necessary for proper bud-site selection in yeast.
SourceNature 365:269-274(1993).
PubMed ID8371782

5AuthorsDownward J.
TitlePlugging the GAPs.
SourceCurr. Biol. 1:353-355(1991).
PubMed ID15336077

6AuthorsGaul U. Mardon G. Rubin G.M.
TitleA putative Ras GTPase activating protein acts as a negative regulator of signaling by the Sevenless receptor tyrosine kinase.
SourceCell 68:1007-1019(1992).
PubMed ID1547500

7AuthorsMaekawa M. Li S. Iwamatsu A. Morishita T. Yokota K. Imai Y. Kohsaka S. Nakamura S. Hattori S.
TitleA novel mammalian Ras GTPase-activating protein which has phospholipid-binding and Btk homology regions.
SourceMol. Cell. Biol. 14:6879-6885(1994).
PubMed ID7935405

8AuthorsWeissbach L. Settleman J. Kalady M.F. Snijders A.J. Murthy A.E. Yan Y.X. Bernards A.
TitleIdentification of a human rasGAP-related protein containing calmodulin-binding motifs.
SourceJ. Biol. Chem. 269:20517-20521(1994).
PubMed ID8051149

9AuthorsBoguski M.S. McCormick F.
TitleProteins regulating Ras and its relatives.
SourceNature 366:643-654(1993).
PubMed ID8259209

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