ArticleProceedings of the National Academy of Sciences of the United States of America2020
Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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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.
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Who cites it
39 citing papers in PubMed, 56 citations in OpenAlex.
- Regulation of Membrane Association and Downstream Effector Interaction of K-Ras by Its Hypervariable Region.Membranes · 2026Article
- AI-Revealed Transition From Density- to Connectivity-Controlled Mechanics in Hierarchical Porous Materials.Small (Weinheim an der Bergstrasse, Germany) · 2026Article
- High yield production of C-terminally processed KRAS4a, HRAS, and NRAS for biophysical study.Protein expression and purification · 2026Article
- KRAS G12C and KRAS G12D respond to lipid metabolism in an allele-specific manner.Journal of lipid research · 2026Article
- Recommendations and considerations for hydroxyl radical protein footprinting-mass spectrometry.Nature methods · 2026Review
- Binding orientation of weakly associating membrane peripheral proteins via membrane paramagnetic relaxation enhancement NMR.Communications chemistry · 2026Article
- Positive cooperativity between RAS-binding and cysteine-rich domains regulates RAF membrane binding kinetics via lateral rebinding.Nature communications · 2026Article
- Recent breakthroughs in understanding the allosteric features of Ras GTPases and their effector and regulatory protein interactions, enabling drug design.Current opinion in structural biology · 2026Review
- Dynamics and lipid membrane coupling of the RAS-RAF complex revealed via multiscale simulations.Biophysical journal · 2026Article
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
- Article
- Mass Spectrometry-Based Protein Footprinting for Protein Structure Characterization.Accounts of chemical research · 2025Article
- KRas4b-Calmodulin Interaction with Membrane Surfaces: Role of Headgroup, Acyl Chain, and Electrostatics.Biochemistry · 2024Article
- Nanodiscs for the study of membrane proteins.Current opinion in structural biology · 2024Review
- Natural Product Graveoline Modulates Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Membrane Association: Insights from Advanced Spectroscopic Studies.ACS pharmacology & translational science · 2024Article
- Adapting recombinant bacterial alkaline phosphatase for nucleotide exchange of small GTPases.Protein expression and purification · 2024Article
- Conserved allosteric perturbation of the GTPase domains by region 1 of Ras hypervariable regions.Biophysical journal · 2024Article
- Membrane lipids drive formation of KRAS4b-RAF1 RBDCRD nanoclusters on the membrane.Communications biology · 2024Article
- Myr-Arf1 conformational flexibility at the membrane surface sheds light on the interactions with ArfGAP ASAP1.Nature communications · 2023Article
- Revealing KRas4b topology on the membrane surface.Biochemical and biophysical research communications · 2023Article
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29 authors at 8 institutions in 1 country.
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Abstract
The small GTPase KRAS is localized at the plasma membrane where it functions as a molecular switch, coupling extracellular growth factor stimulation to intracellular signaling networks. In this process, KRAS recruits effectors, such as RAF kinase, to the plasma membrane where they are activated by a series of complex molecular steps. Defining the membrane-bound state of KRAS is fundamental to understanding the activation of RAF kinase and in evaluating novel therapeutic opportunities for the inhibition of oncogenic KRAS-mediated signaling. We combined multiple biophysical measurements and computational methodologies to generate a consensus model for authentically processed, membrane-anchored KRAS. In contrast to the two membrane-proximal conformations previously reported, we identify a third significantly populated state using a combination of neutron reflectivity, fast photochemical oxidation of proteins (FPOP), and NMR. In this highly populated state, which we refer to as "membrane-distal" and estimate to comprise ∼90% of the ensemble, the G-domain does not directly contact the membrane but is tethered via its C-terminal hypervariable region and carboxymethylated farnesyl moiety, as shown by FPOP. Subsequent interaction of the RAF1 RAS binding domain with KRAS does not significantly change G-domain configurations on the membrane but affects their relative populations. Overall, our results are consistent with a directional fly-casting mechanism for KRAS, in which the membrane-distal state of the G-domain can effectively recruit RAF kinase from the cytoplasm for activation at the membrane.
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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.