ArticleThe Journal of biological chemistry2015
Mechanisms of membrane binding of small GTPase K-Ras4B farnesylated hypervariable region.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 112 citations in OpenAlex.
- Lipid nanoparticles as active biointerfaces: From membrane interaction to systemic dysregulation.Acta pharmaceutica Sinica. B · 2026Review
- Farnesol and geranylgeraniol in plant reproduction: insights from Arabidopsis and beyond.Journal of experimental botany · 2026Review
- Enzymatic Prenylation of Proteins and Peptides: From Cysteine S-Prenylation to Tryptophan-Selective Biocatalysis.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Review
- Mechanistic insights on spatiotemporal control of Ras-signaling.Biological chemistry · 2026Review
- Phosphorylation induces altered protonation states and allosterically regulates Rac1-RhoGDI complex.Protein science : a publication of the Protein Society · 2026Article
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
- RAS-membrane interaction and oligomerization: there is more than meets the eye.Biochemical Society transactions · 2025Review
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Differential functions of the KRAS splice variants.Biochemical Society transactions · 2023Review
- The oncogenic potential of Rab-like protein 1A (RBEL1A) GTPase: The first review of RBEL1A research with future research directions and challenges.Journal of Cancer · 2023Review
- Phosphatidylserine and Phosphatidylethanolamine Asymmetry Have a Negligible Effect on the Global Structure, Dynamics, and Interactions of the KRAS Lipid Anchor.The journal of physical chemistry. B · 2022Article
- The mechanism of activation of MEK1 by B-Raf and KSR1.Cellular and molecular life sciences : CMLS · 2022Article
- In Silico Drug Design of Benzothiadiazine Derivatives Interacting with Phospholipid Cell Membranes.Membranes · 2022Article
- The role of KRAS splice variants in cancer biology.Frontiers in cell and developmental biology · 2022Review
- Post-translational modification of RAS proteins.Current opinion in structural biology · 2021Review
- Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators.Acta pharmaceutica Sinica. B · 2021Review
- Synthetic design of farnesyl-electrostatic peptides for development of a protein kinase A membrane translocation switch.Scientific reports · 2021Article
- Ras isoform-specific expression, chromatin accessibility, and signaling.Biophysical reviews · 2021Review
- The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane.iScience · 2021Article
- Revealing the activation mechanism of autoinhibited RalF by integrated simulation and experimental approaches.Scientific reports · 2021Article
15 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
K-Ras4B belongs to a family of small GTPases that regulates cell growth, differentiation and survival. K-ras is frequently mutated in cancer. K-Ras4B association with the plasma membrane through its farnesylated and positively charged C-terminal hypervariable region (HVR) is critical to its oncogenic function. However, the structural mechanisms of membrane association are not fully understood. Here, using confocal microscopy, surface plasmon resonance, and molecular dynamics simulations, we observed that K-Ras4B can be distributed in rigid and loosely packed membrane domains. Its membrane binding domain interaction with phospholipids is driven by membrane fluidity. The farnesyl group spontaneously inserts into the disordered lipid microdomains, whereas the rigid microdomains restrict the farnesyl group penetration. We speculate that the resulting farnesyl protrusion toward the cell interior allows oligomerization of the K-Ras4B membrane binding domain in rigid microdomains. Unlike other Ras isoforms, K-Ras4B HVR contains a single farnesyl modification and positively charged polylysine sequence. The high positive charge not only modulates specific HVR binding to anionic phospholipids but farnesyl membrane orientation. Phosphorylation of Ser-181 prohibits spontaneous farnesyl membrane insertion. The mechanism illuminates the roles of HVR modifications in K-Ras4B targeting microdomains of the plasma membrane and suggests an additional function for HVR in regulation of Ras signaling.
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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.