Isoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D
Open accessAbstract
Ras GTPases are mutated at codons 12, 13, and 61, with different frequencies in KRas, HRas, and NRas and in a cancer-specific manner. The G13D mutant appears in 25% of KRas-driven colorectal cancers, while observed only rarely in HRas or NRas. Structures of Ras G13D in the three isoforms show an open active site, with adjustments to the D13 backbone torsion angles and with disconnected switch regions. KRas G13D has unique features that destabilize the nucleotide-binding pocket. In KRas G13D bound to GDP, A59 is placed in the Mg 2+ binding site, as in the HRas-SOS complex. Structure and biochemistry are consistent with an intermediate level of KRas G13D bound to GTP, relative to wild-type and KRas G12D, observed in genetically engineered mouse models. The results explain in part the elevated frequency of the G13D mutant in KRas over the other isoforms of Ras.
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Mutant forms of KRAS produce distinct molecular and cellular phenotypes that are largely dependent upon the tissue context.
“mutant forms of KRAS produce distinct molecular and cellular phenotypes that are largely dependent upon the tissue context4,78,79”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [79]
KRAS (G13D) enhances nucleotide exchange.
“For example, KRAS (G13D) enhances nucleotide exchange.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [153]
These rapid exchange mutations may deplete the activity of GEF, thereby desensitizing cancer cells to GEF inhibition.
“However, these rapid exchange mutations may deplete the activity of GEF, thereby desensitizing cancer cells to GEF inhibition [152–154].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [153]
Rapid exchange mutants can synergize with GEF to produce extremely high levels of nucleotide exchange.
“Rapid exchange mutants can synergize with GEF to produce extremely high levels of nucleotide exchange.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [153]
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References 68 · Cited by 89
- Authors
- Johnson, C. W., Lin, Y.-J., Reid, D., Parker, J., Pavlopoulos, S., Dischinger, P., Graveel, C., Aguirre, A. J., Steensma, M., Haigis, K. M., & Mattos, C.
- Affiliations
- Northeastern University (US)
- Beth Israel Deaconess Medical Center (US)
- Van Andel Institute (US)
- Broad Institute (US)
- Corresponding author
- Steensma, Matthew
- Haigis, Kevin M.
- Mattos, Carla
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 28
- Issue
- 6
- Pages
- 1538-1550.e7
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6709685
- OpenAlex
- W2965941158
- Cited by
- 89
- References
- 68
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 13 · 2023: 16 · 2022: 15 · 2021: 13 · 2020: 13 · 2019: 3
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health
- National Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- KRAS G13D, Ras GTPase, Ras isoforms, switch regions, colorectal cancer, RAS mutations, protein structure
- MeSH terms
- Animals, Colon, Female, Homeostasis, Humans, Hydrolysis, Intestinal Mucosa, Male, Models, Molecular, Mutation, Protein Conformation, Structure-Activity Relationship, Proto-Oncogene Proteins p21(ras), Protein Isoforms, Catalytic Domain, Cell Line, Tumor, Mice, Protein Stability
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