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There is now a CONTENT FREEZE for Mercury while we switch to a new platform. It began on Friday, March 10 at 6pm and will end on Wednesday, March 15 at noon. No new content can be created during this time, but all material in the system as of the beginning of the freeze will be migrated to the new platform, including users and groups. Functionally the new site is identical to the old one. webteam@gatech.edu
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Prof. Carla Mattos, North Carolina State University
Intrinsic hydrolysis in Ras functions through an allosteric switch in the Ras/Raf/MEK/ERK signal transduction pathway
Biochemistry Seminar Series
Ras is a key protein in cellular signal transduction. Mutants of G12 and Q61 impair GTPase activity and are found prominently in cancers. In wild type an allosteric switch promotes disorder to order transition in switch II, placing Q61 near water 189 in the active site. We show that the âonâ and âoffâ conformations of the allosteric switch can also be attained in RasG12V and RasQ61L. The âonâ state in both mutants disallows water 189 and proper placing of Q61 (or lack thereof). While the âoffâ state in RasG12V is disordered like wild type, that in RasQ61L stabilizes an anticatalytic conformation in the presence of Raf. Using a combination of structural analysis, hydrolysis rates in the presence and absence of Raf and experiments in NIH-3T3 cells we link the allosteric switch to the control of signaling in the Ras/Raf/MEK/ERK pathway. Furthermore, we have captured a transition state mimic for the intrinsic hydrolysis reaction using AlF3 bound to an allosteric site mutant that stabilizes the âonâ state of the allosteric switch.
For more information contact Prof. Raquel Lieberman (404-385-3663).
