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The arginine finger of RasGAP helps Gln-61 align the nucleophilic water in GAP-stimulated hydrolysis of GTP
Proceedings of the National Academy of Sciences - PNAS, Vol.98(11), pp.6033-6038
The National Academy of Sciences
05/22/2001
Handle:
https://hdl.handle.net/2376/110674
PMCID: PMC33417
PMID: 11371635
Abstract
The Ras family of GTPases is a collection of molecular switches
that link receptors on the plasma membrane to signaling pathways that
regulate cell proliferation and differentiation. The accessory
GTPase-activating proteins (GAPs) negatively regulate the cell
signaling by increasing the slow intrinsic GTP to GDP hydrolysis rate
of Ras. Mutants of Ras are found in 25–30% of human tumors. The most
dramatic property of these mutants is their insensitivity to the
negative regulatory action of GAPs. All known oncogenic mutants of Ras
map to a small subset of amino acids. Gln-61 is particularly important
because virtually all mutations of this residue eliminate sensitivity
to GAPs. Despite its obvious importance for carcinogenesis, the role of
Gln-61 in the GAP-stimulated GTPase activity of Ras has remained a
mystery. Our molecular dynamics simulations of the p21ras–p120GAP–GTP
complex suggest that the local structure around the catalytic region
can be different from that revealed by the x-ray crystal structure. We
find that the carbonyl oxygen on the backbone of the arginine finger
supplied in trans by p120GAP (Arg-789) interacts with a water molecule
in the active site that is forming a bridge between the NH2
group of the Gln-61 and the γ-phosphate of GTP. Thus, Arg-789 may
play a dual role in generating the nucleophile as well as stabilizing
the transition state for P—O bond cleavage.
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Details
- Title
- The arginine finger of RasGAP helps Gln-61 align the nucleophilic water in GAP-stimulated hydrolysis of GTP
- Creators
- Haluk ResatT. P StraatsmaDavid A DixonJohn H Miller
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.98(11), pp.6033-6038
- Academic Unit
- Engineering and Applied Sciences (TRIC), School of
- Publisher
- The National Academy of Sciences
- Identifiers
- 99900547112101842
- Language
- English
- Resource Type
- Other