Evidence map›Paper›PMID 41651414›Full record

ArticleThe Journal of biological chemistry2026

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

Konstantia Georgouli, Jeremy O B Tempkin, Liam G Stanton, Tomas Oppelstrup, Rebika Shrestha, Timothy S Carpenter, Fikret Aydin, Xiaohua Zhang, Harsh Bhatia, Yue Yang and 24 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of biological chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

34 authors.

Konstantia GeorgouliPhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Jeremy O B TempkinPhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Liam G StantonDepartment of Mathematics and Statistics, San José State University, San José, California, USA.
Tomas OppelstrupPhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Rebika ShresthaNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Timothy S CarpenterPhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Fikret AydinPhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Xiaohua ZhangPhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Harsh BhatiaComputing Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Yue YangPhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Que N VanNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Pedro Andrade BonillaNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Gulcin GultenNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Debanjan GoswamiNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Francesco Di NataleComputing Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Joseph R ChavezComputing Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Joseph Y MoonComputing Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Gautham DharumanPhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Nicolas W HengartnerTheoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
Dhirendra K SimanshuNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Timothy H TranNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Kien NguyenTheoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
Christopher B StanleyComputational Sciences and Engineering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA.
Brian Van EssenComputing Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Peer-Timo BremerComputing Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Felice C LightstonePhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Andrew G StephenNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
James N GlosliPhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
Sandrasegaram GnanakaranTheoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
Thomas J TurbyvilleNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Frank McCormickNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
Dwight V NissleyNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. Electronic address: nissleyd@mail.nih.gov.
Frederick H StreitzComputing Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA. Electronic address: streitz1@llnl.gov.
Helgi I IngólfssonPhysical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA. Electronic address: ingolfsson1@llnl.gov.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Cell MembraneLipidsProto-Oncogene Proteins p21(ras)raf KinasesHumansMolecular Dynamics SimulationKRAS protein, humanLipidsProto-Oncogene Proteins p21(ras)raf KinasesKRAS4aKRAS4bKRAS functionmassive parallel simulationsmultiscale modelingRAS-membrane biologyRAS-RBDCRD membrane dynamicsRBDCRD of RAF

Identifiers

PMID41651414
PMCPMC12969416

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.