ArticleBiophysical journal2016
Oncogenic K-Ras Binds to an Anionic Membrane in Two Distinct Orientations: A Molecular Dynamics Analysis.
Article in Biophysical journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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89 citing papers in PubMed.
- Regulation of Membrane Association and Downstream Effector Interaction of K-Ras by Its Hypervariable Region.Membranes · 2026Article
- KRAS G12C and KRAS G12D respond to lipid metabolism in an allele-specific manner.Journal of lipid research · 2026Article
- Rheb membrane orientation dynamics and functional consequences elucidated by molecular simulations, single-molecule-FRET and signaling assays.bioRxiv : the preprint server for biology · 2026Article
- KRAS4a and KRAS4b show distinct lipid-dependent regulation of RAS-RAF membrane dynamics.The Journal of biological chemistry · 2026Article
- Dynamics and lipid membrane coupling of the RAS-RAF complex revealed via multiscale simulations.Biophysical journal · 2026Article
- RAS-membrane interaction and oligomerization: there is more than meets the eye.Biochemical Society transactions · 2025Review
- Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Atomistic simulations reveal impacts of missense mutations on the structure and function of SynGAP1.Briefings in bioinformatics · 2024Article
- From disorder comes function: Regulation of small GTPase function by intrinsically disordered lipidated membrane anchor.Current opinion in structural biology · 2024Review
- KRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways.Cells · 2024Review
- Intrinsically Disordered Membrane Anchors of Rheb, RhoA, and DiRas3 Small GTPases: Molecular Dynamics, Membrane Organization, and Interactions.The journal of physical chemistry. B · 2024Article
- RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains.The Journal of cell biology · 2024Article
- Decrypting Allostery in Membrane-Bound K-Ras4B Using ComplementaryJournal of the American Chemical Society · 2024Article
- Deciphering Lipid Arrangement in Phosphatidylserine/Phosphatidylcholine Mixed Membranes: Simulations and Experiments.Langmuir : the ACS journal of surfaces and colloids · 2023Article
- Membrane anchoring of the DIRAS3 N-terminal extension permits tumor suppressor function.iScience · 2023Article
- Conformational ensemble-dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small GTPases.Communications biology · 2023Article
- A new ferrocene derivative blocks K-Ras localization and function by oxidative modification at His95.Life science alliance · 2023Article
- Revealing KRas4b topology on the membrane surface.Biochemical and biophysical research communications · 2023Article
- Article
29 more citing papers are in PubMed but not listed here.
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5 authors.
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Abstract
K-Ras is a membrane-associated GTPase that cycles between active and inactive conformational states to regulate a variety of cell signaling pathways. Somatic mutations in K-Ras are linked to 15-20% of all human tumors. K-Ras attaches to the inner leaflet of the plasma membrane via a farnesylated polybasic domain; however, the structural details of the complex remain poorly understood. Based on extensive (7.5 μs total) atomistic molecular dynamics simulations here we show that oncogenic mutant K-Ras interacts with a negatively charged lipid bilayer membrane in multiple orientations. Of these, two highly populated orientations account for ∼54% of the conformers whose catalytic domain directly interacts with the bilayer. In one of these orientation states, membrane binding involves helices 3 and 4 of the catalytic domain in addition to the farnesyl and polybasic motifs. In the other orientation, β-strands 1-3 and helix 2 on the opposite face of the catalytic domain contribute to membrane binding. Flexibility of the linker region was found to be important for the reorientation. The biological significance of these observations was evaluated by initial experiments in cells overexpressing mutant K-Ras as well as by an analysis of Ras-effector complex structures. The results suggest that only one of the two major orientation states is capable of effector binding. We propose that the different modes of membrane binding may be exploited in structure-based drug design efforts for cancer therapy.
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