ArticleeLife2022
A saturation-mutagenesis analysis of the interplay between stability and activation in Ras.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 26 citations in OpenAlex.
- Redesign of energetically frustrated regions rescues function in defective T4 clamp loaders.Molecular biology and evolution · 2026Article
- Dual functional genomics reveals a broad and convergent landscape of asciminib resistance in BCR::ABL1.Genome medicine · 2026Article
- Functional dissection ofProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Staphylococcus aureus sensor histidine kinase VraS mutations linked to antibiotic resistance affect enzymatic catalysis, stability, and substrate interactions.Archives of biochemistry and biophysics · 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
- Functional Analysis of Rare RAS Variants of Unknown Significance.Cancer research communications · 2025Article
- Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity.Nature communications · 2025Article
- Allosteric modulation of NF1 GAP: Differential distributions of catalytically competent populations in loss-of-function and gain-of-function mutants.Protein science : a publication of the Protein Society · 2025Article
- Conditional requirement for dimerization of the membrane-binding module for BTK signaling in lymphocyte cell lines.Science signaling · 2025Article
- M-Ras distinct activation scenarios: A mechanistic outlook and targeting.Computational and structural biotechnology journal · 2025Article
- Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity.bioRxiv : the preprint server for biology · 2024Article
- Functional distinction in oncogenic Ras variant activity in Caenorhabditis elegans.Disease models & mechanisms · 2024Article
- Structure-based network analysis predicts pathogenic variants in human proteins associated with inherited retinal disease.NPJ genomic medicine · 2024Article
- Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis.Nature communications · 2024Article
- Article
- RAS signaling and immune cells: a sinister crosstalk in the tumor microenvironment.Journal of translational medicine · 2023Review
- Emerging maps of allosteric regulation in cellular networks.Current opinion in structural biology · 2023Review
- A complete allosteric map of a GTPase switch in its native cellular network.Cell systems · 2023Article
- Saturation mutagenesis of a predicted ancestral Syk-family kinase.Protein science : a publication of the Protein Society · 2022Article
- A saturation-mutagenesis analysis of the interplay between stability and activation in Ras.eLife · 2022Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Cancer mutations in Ras occur predominantly at three hotspots: Gly 12, Gly 13, and Gln 61. Previously, we reported that deep mutagenesis of H-Ras using a bacterial assay identified many other activating mutations (Bandaru et al., 2017). We now show that the results of saturation mutagenesis of H-Ras in mammalian Ba/F3 cells correlate well with the results of bacterial experiments in which H-Ras or K-Ras are co-expressed with a GTPase-activating protein (GAP). The prominent cancer hotspots are not dominant in the Ba/F3 data. We used the bacterial system to mutagenize Ras constructs of different stabilities and discovered a feature that distinguishes the cancer hotspots. While mutations at the cancer hotspots activate Ras regardless of construct stability, mutations at lower-frequency sites (e.g. at Val 14 or Asp 119) can be activating or deleterious, depending on the stability of the Ras construct. We characterized the dynamics of three non-hotspot activating Ras mutants by using NMR to monitor hydrogen-deuterium exchange (HDX). These mutations result in global increases in HDX rates, consistent with destabilization of Ras. An explanation for these observations is that mutations that destabilize Ras increase nucleotide dissociation rates, enabling activation by spontaneous nucleotide exchange. A further stability decrease can lead to insufficient levels of folded Ras - and subsequent loss of function. In contrast, the cancer hotspot mutations are mechanism-based activators of Ras that interfere directly with the action of GAPs. Our results demonstrate the importance of GAP surveillance and protein stability in determining the sensitivity of Ras to mutational activation.
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