Unveiling the Dynamics of KRAS4b on Lipid Model Membranes

López, Cesar A.; Agarwal, Animesh; Van, Que N.; Stephen, Andrew G.; Gnanakaran, S.

doi:10.1007/s00232-021-00176-z

Title: Unveiling the Dynamics of KRAS4b on Lipid Model Membranes

Journal Article · 06 April 2021 · Journal of Membrane Biology

DOI: https://doi.org/10.1007/s00232-021-00176-z · OSTI ID:1774699

; Agarwal, Animesh; Van, Que N.; Stephen, Andrew G.; Gnanakaran, S.

Abstract Small GTPase proteins are ubiquitous and responsible for regulating several processes related to cell growth and differentiation. Mutations that stabilize their active state can lead to uncontrolled cell proliferation and cancer. Although these proteins are well characterized at the cellular scale, the molecular mechanisms governing their functions are still poorly understood. In addition, there is limited information about the regulatory function of the cell membrane which supports their activity. Thus, we have studied the dynamics and conformations of the farnesylated KRAS4b in various membrane model systems, ranging from binary fluid mixtures to heterogeneous raft mimics. Our approach combines long time-scale coarse-grained (CG) simulations and Markov state models to dissect the membrane-supported dynamics of KRAS4b. Our simulations reveal that protein dynamics is mainly modulated by the presence of anionic lipids and to some extent by the nucleotide state (activation) of the protein. In addition, our results suggest that both the farnesyl and the polybasic hypervariable region (HVR) are responsible for its preferential partitioning within the liquid-disordered (Ld) domains in membranes, potentially enhancing the formation of membrane-driven signaling platforms. Graphic Abstract

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

Sponsoring Organization:: National Cancer Institute (NCI); USDOE Advanced Research Projects Agency - Energy (ARPA-E)

Grant/Contract Number:: 89233218CNA000001; AC02-06CH11357; AC05-00OR22725; AC52-06NA25396; AC52-07NA27344

OSTI ID:: 1774699

Report Number(s):: LA-UR--20-26792; PII: 176

Journal Information:: Journal of Membrane Biology, Journal Name: Journal of Membrane Biology Journal Issue: 2 Vol. 254; ISSN 0022-2631

Publisher:: Springer Science + Business MediaCopyright Statement

Country of Publication:: United States

Language:: English

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