Methionine 170 is an Environmentally Sensitive Membrane Anchor in the Disordered HVR of K-Ras4B

Neale, Christopher Andrew; García, Angel Enrique

doi:10.1021/acs.jpcb.8b07919

Title: Methionine 170 is an Environmentally Sensitive Membrane Anchor in the Disordered HVR of K-Ras4B

Journal Article · 15 October 2018 · Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry

DOI: https://doi.org/10.1021/acs.jpcb.8b07919 · OSTI ID:1480050

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Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Ras protein colocalization at the plasma membrane is implicated in the activation of signaling cascades that promote cell growth, survival, and motility. However, the mechanisms that underpin Ras self-association remain unclear. We use molecular dynamics simulations to show how basic and hydrophobic components of the disordered C-terminal membrane tether of K-Ras4B combine to regulate its membrane interactions. Specifically, anionic lipids attract lysine residues to the membrane surface, thereby splitting the peptide population into two states that exchange on the microsecond time scale. These states differ in the membrane insertion of a methionine residue, which is influenced by local membrane composition. As a result, these states may impose context-dependent biases on the disposition of Ras’ signaling domain, with possible implications for the accessibility of its effector binding surfaces. Furthermore, we investigate Ras’ ability to nanocluster by fly-casting for patches of anionic lipids and find that while anionic lipids promote the intermolecular association of K-Ras4B membrane tethers, at short range this appears to be a passive process in which anionic lipids electrostatically screen these cationic peptides to mitigate their natural repulsion. Together with the sub-microsecond stability of interpeptide contacts, this result suggests that experimentally observed K-Ras4B nanoclustering is not driven by direct intermolecular contact of its membrane tethers.

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Research Organization:: Los Alamos National Laboratory (LANL)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1480050

Report Number(s):: LA-UR-18-27534

Journal Information:: Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry, Journal Name: Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry Journal Issue: 44 Vol. 122; ISSN 1520-6106

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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AI Meets Exascale Computing: Advancing Cancer Research With Large-Scale High Performance Computing Bhattacharya, Tanmoy; Brettin, Thomas; Doroshow, James H. Frontiers in Oncology, Vol. 9 https://doi.org/10.3389/fonc.2019.00984	journal	October 2019
Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior Goswami, Debanjan; Chen, De; Yang, Yue eLife, Vol. 9 https://doi.org/10.7554/elife.47654	journal	January 2020

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