The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling

Neale, Chris; García, Angel E.

doi:10.1016/j.bpj.2019.12.039

Cited by 56Protein Kinase Regulation and GTPase SignalingLipid Membrane Structure and BehaviorCellular transport and secretion

The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling

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Neale, Chris, García, Angel E.·2020·Biophysical Journal

DOI 10.1016/j.bpj.2019.12.039PMC PMC7063485

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Abstract

Mutant Ras proteins are important drivers of human cancers, yet no approved drugs act directly on this difficult target. Over the last decade, the idea has emerged that oncogenic signaling can be diminished by molecules that drive Ras into orientations in which effector-binding interfaces are occluded by the cell membrane. To support this approach to drug discovery, we characterize the orientational preferences of membrane-bound K-Ras4B in 1.45-ms aggregate time of atomistic molecular dynamics simulations. Individual simulations probe active or inactive states of Ras on membranes with or without anionic lipids. We find that the membrane orientation of Ras is relatively insensitive to its bound guanine nucleotide and activation state but depends strongly on interactions with anionic phosphatidylserine lipids. These lipids slow Ras' translational and orientational diffusion and promote a discrete population in which small changes in orientation control Ras' competence to bind multiple regulator and effector proteins. Our results suggest that compound-directed conversion of constitutively active mutant Ras into functionally inactive forms may be accessible via subtle perturbations of Ras' orientational preferences at the membrane surface.

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The orientation of one protein to the membrane can expose or hide protein binding sites and thus regulate signal progression through the pathway.
“Furthermore, the orientation of one protein to the membrane can expose or hide protein binding sites and thus regulate signal progression through the pathway [290].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [290]

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Authors: Neale, C., & García, A. E.
Affiliations: Los Alamos National Laboratory (US)
ORCID: Neale, Chris
Venue: Biophysical Journal
Publisher: Elsevier BV
Published: 2020-03
Volume: 118
Issue: 5
Pages: 1129-1141
ISSN: 0006-3495 (ISSN-L)
DOI: 10.1016/j.bpj.2019.12.039
PMC: PMC7063485
OpenAlex: W3000950504
Cited by: 56
References: 98
Citations by year: 2026: 6 · 2025: 7 · 2024: 4 · 2023: 3 · 2022: 10 · 2021: 13 · 2020: 13
FWCI: 3.16
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 374 d)
Locations: Biophysical Journal (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders: US Department of Energy
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords: K-Ras4B, plasma membrane, oncogenic Ras, competitive inhibitors, positive allosteric modulators, guanine nucleotide binding
MeSH terms: Cell Membrane, Humans, Phosphatidylserines, Signal Transduction, Proto-Oncogene Proteins p21(ras), ras Proteins, Molecular Dynamics Simulation

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The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling

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