KRAS4a and KRAS4b show distinct lipid-dependent regulation of RAS-RAF membrane dynamics

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.

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Publication Details

Journal
Journal of Biological Chemistry
Published
2026-02-05
DOI
https://doi.org/10.1016/j.jbc.2026.111237
Primary Topic
Lipid Membrane Structure and Behavior
Type
article
Field-Weighted Citation Impact
0.00

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article

KRAS4a and KRAS4b show distinct lipid-dependent regulation of RAS-RAF membrane dynamics

Helgi I. Ingólfsson, Francesco Di Natale, Pedro Andrade Bonilla, Debanjan Goswami et al.
Journal of Biological Chemistry
Lipid Membrane Structure and Behavior
article

KRAS4a and KRAS4b show distinct lipid-dependent regulation of RAS-RAF membrane dynamics

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

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.

Journal of Biological ChemistryVol. 302(3)
Lawrence Livermore National Laboratory (US), Oak Ridge National Laboratory (US), Los Alamos National Laboratory (US), Frederick National Laboratory for Cancer Research (US), Lawrence Livermore National Security (US), Center for Cancer Research (US), UCSF Helen Diller Family Comprehensive Cancer Center (US), San Jose State University (US)
U.S. Department of Energy, Frederick National Laboratory for Cancer Research, National Institutes of Health, Office of Science, National Nuclear Security Administration, National Cancer Institute, Advanced Scientific Computing Research, Argonne National Laboratory, Lawrence Livermore National Laboratory, Oak Ridge National Laboratory, Los Alamos National Laboratory
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Lipid Membrane Structure and Behavior
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