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J. Biol. Chem., Vol. 280, Issue 27, 25697-25705, July 8, 2005

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Structure of the G60A Mutant of Ras

IMPLICATIONS FOR THE DOMINANT NEGATIVE EFFECT^*

Bradley Ford, Karlheinz Skowronek¶, Sean Boykevisch||, Dafna Bar-Sagi||, and Nicolas Nassar**

From the Departments of Physiology and Biophysics and ^||Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794-8661

Substituting alanine for glycine at position 60 in v-H-Ras generated a dominant negative mutant that completely abolished the ability of v-H-Ras to transform NIH 3T3 cells and to induce germinal vesicle breakdown in Xenopus oocytes. The crystal structure of the GppNp-bound form of RasG60A unexpectedly shows that the switch regions adopt an open conformation reminiscent of the structure of the nucleotide-free form of Ras in complex with Sos. Critical residues that normally stabilize the guanine nucleotide and the Mg²⁺ ion have moved considerably. Sos binds to RasG60A but is unable to catalyze nucleotide exchange. Our data suggest that the dominant negative effect observed for RasG60A·GTP could result from the sequestering of Sos in a non-productive Ras-GTP-guanine nucleotide exchange factor ternary complex.

Received for publication, February 28, 2005 , and in revised form, April 19, 2005.

The atomic coordinates and structure factors (codes 1XJ0 and 1XCM for RasG60A in the GDP- and GppNp-bound forms, respectively) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by National Science Foundation Grant MCB-0316600, the Philip Morris Research Management Group, and an Innovative Technology Development grant (to N. N.). The National Synchrotron Light Source is supported by the Department of Energy and National Institutes of Health, and beamline X26C is supported in part by Stony Brook University and its Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Medical Scientist Training Grant.

^¶ Supported by National Research Service Award T32-DK07521-16 funded by the NIDDK, National Institutes of Health.

^** To whom correspondence should be addressed: Dept. of Physiology and Biophysics, Basic Sciences Tower, Stony Brook University, Stony Brook, NY 11794-8661. Tel.: 631-444-3521; Fax: 631-444-3432; E-mail: nicolas.nassar{at}sunysb.edu.

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