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Published March 7, 2003 | public
Journal Article

Structural Evidence for Feedback Activation by Ras·GTP of the Ras-Specific Nucleotide Exchange Factor SOS


Growth factor receptors activate Ras by recruiting the nucleotide exchange factor son of sevenless (SOS) to the cell membrane, thereby triggering the production of GTP-loaded Ras. Crystallographic analyses of Ras bound to the catalytic module of SOS have led to the unexpected discovery of a highly conserved Ras binding site on SOS that is located distal to the active site and is specific for Ras·GTP. The crystal structures suggest that Ras·GTP stabilizes the active site of SOS allosterically, and we show that Ras·GTP forms ternary complexes with SOS^(cat) in solution and increases significantly the rate of SOS^(cat)-stimulated nucleotide release from Ras. These results demonstrate the existence of a positive feedback mechanism for the spatial and temporal regulation of Ras.

Additional Information

© 2003 Cell Press. Received 3 December 2002, Revised 24 January 2003, Available online 10 March 2003. We thank Nicholas Nasser for helpful comments and sharing data prior to publication; Sandhya Visweswariah for help with the purification and crystallization of the RasY64A complex; David King for mass spectrometry; Andrew Elliott and Jack Kirsch for help with fluorescence spectroscopy; and the beamline scientists at the Advanced Light Source, the Advanced Photon Source, and the Cornell High Energy Synchrotron Source for their invaluable assistance. Support from the following agencies is gratefully acknowledged: NIH (D.B.-S.), Leukemia and Lymphoma Society (H.S.), Human Frontiers Science Program (B.N.), and Burroughs Welcome Fund (A.H.). Accession Numbers: Crystallographic coordinates and structure factors have been deposited in the Protein Data Bank under accession codes 1NVV, 1NVU, 1NVW, and 1NVX.

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