Molecular recognition of RAS/RAF complex at the membrane: Role of RAF cysteine-rich domain

Travers, Timothy; Lopez Bautista, Cesar Augusto; Van, Que; Neale, Christopher Andrew; Tonelli, Marco; Stephen, Andrew; Gnanakaran, Sandrasegaram

doi:10.1038/s41598-018-26832-4

Title: Molecular recognition of RAS/RAF complex at the membrane: Role of RAF cysteine-rich domain

Journal Article · Thu May 31 00:00:00 EDT 2018 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-018-26832-4· OSTI ID:1441351

^[1];

^[1]; Van, Que ^[2];

^[1]; Tonelli, Marco ^[3]; Stephen, Andrew ^[2];

^[1]

Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Leidos Biomedical Research, Inc., Frederick, MD (United States). Frederick National Lab. for Cancer Research
Univ. of Wisconsin, Madison, WI (United States). National Magnetic Resource Facility at Madison, Biochemistry Dept.

Activation of RAF kinase involves the association of its RAS-binding domain (RBD) and cysteine-rich domain (CRD) with membrane-anchored RAS. However, the overall architecture of the RAS/RBD/CRD ternary complex and the orientations of its constituent domains at the membrane remain unclear. Here in this paper, we have combined all-atom and coarse-grained molecular dynamics (MD) simulations with experimental data to construct and validate a model of membrane-anchored CRD, and used this as a basis to explore models of membrane-anchored RAS/RBD/CRD complex. First, simulations of the CRD revealed that it anchors to the membrane via insertion of its two hydrophobic loops, which is consistent with our NMR measurements of CRD bound to nanodiscs. Simulations of the CRD in the context of membrane-anchored RAS/RBD then show how CRD association with either RAS or RBD could play an unexpected role in guiding the membrane orientations of RAS/RBD. This finding has implications for the formation of RAS-RAS dimers, as different membrane orientations of RAS expose distinct putative dimerization interfaces.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE Laboratory Directed Research and Development (LDRD) Program; National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: AC52-06NA25396; AC52-07NA27344; AC02-06CH11357; HHSN261200800001E; P41GM103399

OSTI ID:: 1441351

Report Number(s):: LA-UR-18-21268

Journal Information:: Scientific Reports, Vol. 8, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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