GTP-Dependent K-Ras Dimerization
Open accessAbstract
Ras proteins recruit and activate effectors, including Raf, that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, activation of Raf requires its dimerization. It has been suspected that dimeric Ras may promote dimerization and activation of Raf. Here, we show that the GTP-bound catalytic domain of K-Ras4B, a highly oncogenic splice variant of the K-Ras isoform, forms stable homodimers. We observe two major dimer interfaces. The first, highly populated β-sheet dimer interface is at the Switch I and effector binding regions, overlapping the binding surfaces of Raf, PI3K, RalGDS, and additional effectors. This interface has to be inhibitory to such effectors. The second, helical interface also overlaps the binding sites of some effectors. This interface may promote activation of Raf. Our data reveal how Ras self-association can regulate effector binding and activity, and suggest that disruption of the helical dimer interface by drugs may abate Raf signaling in cancer.
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KRAS dimerization is a GTP-dependent process.
“The KRAS dimerization is a GTP-dependent process [67].”
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“Onco-genic KRAS has been identified as a key player in inducing significant metabolic changes in cells and can drive alterations in various metabolic pathways, including glycolysis, glu-Curr taminolysis, and micropinocytosis [24].”
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Plasma membrane regulates Ras signaling networks
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Allosteric activation of RAF in the MAPK signaling pathway
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- Authors
- Muratcioglu, S., Chavan, T. S., Freed, B. C., Jang, H., Khavrutskii, L., Freed, R. N., Dyba, M. A., Stefanisko, K., Tarasov, S. G., Gursoy, A., Keskin, O., Tarasova, N. I., Gaponenko, V., & Nussinov, R.
- Affiliations
- University of Illinois Chicago (US)
- National Cancer Institute (US)
- Frederick National Laboratory for Cancer Research (US)
- Tel Aviv University (IL)
- Corresponding author
- Gaponenko, Vadim
- Nussinov, Ruth
- ORCID
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 23
- Issue
- 7
- Pages
- 1325-1335
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC4497850
- OpenAlex
- W1535997186
- Cited by
- 202
- References
- 52
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 12 · 2023: 15 · 2022: 17 · 2021: 23 · 2020: 27 · 2019: 21 · 2018: 22 · 2017: 15 · 2016: 30 · 2015: 12
- FWCI
- 10.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (HHSN261200800001C)
- National Heart, Lung, and Blood Institute (R21HL118588)
- National Cancer Institute (HHSN261200800001E), R01CA135341)
- 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
- K-Ras4B, GTP-bound Ras, Raf activation, RAF dimerization, dimer interface, switch I, effector binding, phosphatidylinositol 3-kinase, RalGDS, Ras effectors, cancer drug targets
- MeSH terms
- Guanosine Triphosphate, Humans, Kinetics, Protein Binding, Proto-Oncogene Proteins p21(ras), Catalytic Domain, Protein Interaction Domains and Motifs, Protein Multimerization
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