Ras proteins are membrane-associated molecular switches that bind GTP and GDP
and slowly hydrolyze GTP to GDP . 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 .
Neurofibromin (gene NF1) . 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 , which acts as a negative regulator of signalling by
the Sevenless receptor tyrosine kinase involved in eye development.
Mammalian Gap1m , which is related to the drosophila Gap1 protein.
Human IQGAP1 , 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 . 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 ) that do not share sequence
similarity with ras GAPs.
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