Deconstruction of the Ras switching cycle through saturation mutagenesis
Open accessAbstract
Ras proteins are highly conserved signaling molecules that exhibit regulated, nucleotide-dependent switching between active and inactive states. The high conservation of Ras requires mechanistic explanation, especially given the general mutational tolerance of proteins. Here, we use deep mutational scanning, biochemical analysis and molecular simulations to understand constraints on Ras sequence. Ras exhibits global sensitivity to mutation when regulated by a GTPase activating protein and a nucleotide exchange factor. Removing the regulators shifts the distribution of mutational effects to be largely neutral, and reveals hotspots of activating mutations in residues that restrain Ras dynamics and promote the inactive state. Evolutionary analysis, combined with structural and mutational data, argue that Ras has co-evolved with its regulators in the vertebrate lineage. Overall, our results show that sequence conservation in Ras depends strongly on the biochemical network in which it operates, providing a framework for understanding the origin of global selection pressures on proteins.
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RAS mutants were once thought to be locked in the GTP-bound on state and undruggable, but detailed structural and biochemical analyses have revealed differences among RAS mutants in GTPase activity, GDP-GTP exchange and effector binding.
“RAS mutants were once viewed as being ‘locked’ in the GTP-bound ‘on’ state, impervious to GAP-stimulated or intrinsic GTP hydrolysis, and hence undruggable. However, detailed structural and biochemical analyses of various RAS mutants associated with cancer and ‘RASopathies’”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [48]
Some oncogenic KRAS mutants, notably KRASG12C and to a lesser extent KRASG12D, retain significant intrinsic GTPase activity.
“Some oncogenic mutants, notably KRASG12C (G12C) and, to a lesser extent, KRASG12D (G12D), retain significant intrinsic GTPase activity.”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Bandaru et al., 2017
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- Authors
- Bandaru, P., Shah, N. H., Bhattacharyya, M., Barton, J. P., Kondo, Y., Cofsky, J. C., Gee, C. L., Chakraborty, A. K., Kortemme, T., Ranganathan, R., & Kuriyan, J.
- Affiliations
- QB3 (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- University of California, San Francisco (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Ranganathan, Rama
- Kuriyan, John
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-07-07
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5538825
- OpenAlex
- W2727251566
- Cited by
- 117
- References
- 91
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 7 · 2023: 14 · 2022: 16 · 2021: 19 · 2020: 11 · 2019: 11 · 2018: 13 · 2017: 3
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- Ras proteins, deep mutational scanning, saturation mutagenesis, GTPase-activating protein, nucleotide exchange factor, mutational tolerance, sequence conservation
- MeSH terms
- DNA Mutational Analysis, Humans, Mutagenesis, Conserved Sequence, ras Proteins, Evolution, Molecular, Protein Interaction Maps
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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