Publication Date

3-1-2026

Document Type

Article

Publication Title

Journal of Biological Chemistry

Volume

302

Issue

3

DOI

10.1016/j.jbc.2026.111237

Abstract

KRAS4a and KRAS4b are important regulators of signaling, and their interactions with the plasma membrane are dynamic and influenced by lipid composition. KRAS 4a and 4b have nearly identical globular domains but differ in their membrane-associated hyper variable region (HVR). The functional distinctions between these isoforms remain unclear, particularly with regards to their dependence on specific lipids and the membrane environment. Previous work showed that the membrane orientation of KRAS4b affects its ability to bind to RAF kinase RBDCRD and that the KRAS–RBDCRD complex adopts different poses on the membrane as well as influences the size and composition of the lipid environment. To model differences between KRAS 4a and 4b protein–lipid interactions, we extended the Multiscale Machine-Learned Modeling Infrastructure (MuMMI) to incorporate continuum simulations in the grand canonical ensemble, enabling sampling across macroscopic, coarse-grained, and all-atom resolutions. Using this framework, we systematically altered PIP2 concentrations, KRAS 4a versus 4b, and RAF RBDCRD complexation to assess impacts on membrane–protein interactions and dynamics. Our results reveal that reducing PIP2 shifts and broadens the membrane orientational preference of both KRAS 4b and 4a, with stronger effects on 4b HVR localization versus 4a. We demonstrate that with depletion of the strong negatively charged PIP2 lipid, the less charged phosphatidylserine replaces PIP2. Our findings highlight similarities and distinctions in the dynamics and lipid dependency of KRAS isoforms and suggest that ordering of the local lipid composition by HVRs is a shared property and key modulator of RAS-mediated signaling at the plasma membrane.

Funding Number

DE-AC52-06NA25396

Funding Sponsor

National Institutes of Health

Keywords

KRAS function, KRAS4a, KRAS4b, massive parallel simulations, multiscale modeling, RAS-membrane biology, RAS-RBDCRD membrane dynamics, RBDCRD of RAF

Comments

Full author list: Konstantia Georgouli, Jeremy O.B. Tempkin, Liam G. Stanton, Tomas Oppelstrup, Rebika Shrestha, Timothy S. Carpenter, Fikret Aydin, Xiaohua Zhang, Harsh Bhatia, Yue Yang, Que N. Van, Pedro Andrade Bonilla, Gulcin Gulten, Debanjan Goswami, Francesco Di Natale, Joseph R. Chavez, Joseph Y. Moon, Gautham Dharuman, Nicolas W. Hengartner, Dhirendra K. Simanshu, Timothy H. Tran, Kien Nguyen, Christopher B. Stanley, Brian Van Essen, Peer-Timo Bremer, Felice C. Lightstone, Andrew G. Stephen, James N. Glosli, Sandrasegaram Gnanakaran, Thomas J. Turbyville, Frank McCormick, Dwight V. Nissley, Frederick H. Streitz, Helgi I. Ingólfsson

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Department

Mathematics and Statistics

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