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

The Journal of Physical Chemistry Letters
Yang LiKlaus Gerwert

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.

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Citations

Oct 12, 2018·Biochemical Society Transactions·Helen R Mott, Darerca Owen
Jun 21, 2019·PLoS Computational Biology·Ruth NussinovHyunbum Jang
Dec 19, 2018·International Journal of Molecular Sciences·Hendrik SchönebornRolf Heumann
Aug 21, 2020·Cancer Metastasis Reviews·Gyula PálfyAndrás Perczel
Dec 22, 2020·Biophysical Journal·Nurit HaspelRuth Nussinov
May 13, 2021·The Journal of Physical Chemistry. B·Meryem ErenOzlem Keskin
Jun 8, 2021·Chemical Science·Dóra K MenyhárdAndrás Perczel
Sep 15, 2020·Journal of Chemical Theory and Computation·Yuwei ZhangFei Xia

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