Specific Substates of Ras To Interact with GAPs and Effectors: Revealed by Theoretical Simulations and FTIR Experiments.

ABSTRACT: The oncogenic Ras protein adopts various specific conformational states to execute its function in signal transduction. The large number of Ras structures obtained from X-ray and NMR experiments illustrates the diverse conformations that Ras adopts. It is difficult, however, to connect specific structural features with Ras functions. We report the free-energy landscape of Ras·GTP based on extensive explicit solvent simulations. The free-energy map clearly shows that the functional state 2 of Ras·GTP in fact has two distinct substates, denoted here as "Tyr32in" and "Tyr32out". Unbiased MD simulations show that the two substrates interconvert on the submicrosecond scale in solution, pointing to a novel mechanism for Ras·GTP to selectively interact with GAPs and effectors. This proposal is further supported by time-resolved FTIR experiments, which demonstrate that Tyr32 destabilizes the Ras·GAP complex and facilitates an efficient termination of Ras signaling.

SUBMITTER: Li Y 

PROVIDER: S-EPMC6692134 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature