The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
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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“The KRAS dimerization is a GTP-dependent process [67].”
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Cites
Discovery and saturation analysis of cancer genes across 21 tumour types
Lawrence, M. S., Stojanov, P., Mermel, C. H., Robinson, J. T., Garraway, L. A., Golub, T. R., Meyerson, M., Gabriel, S. B., Lander, E. S., & Getz, G. (2014) · Nature · doi:10.1038/nature12912 · Cited by 3,096 · cited 1×
“K-Ras, which is frequently mutated in human cancer (Lawrence et al., 2014), is the most potent activator of Raf among Ras isoforms (Prior et al., 2012).”
BackgroundA Comprehensive Survey of Ras Mutations in Cancer
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“K-Ras, which is frequently mutated in human cancer (Lawrence et al., 2014), is the most potent activator of Raf among Ras isoforms (Prior et al., 2012).”
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RAS Interaction with PI3K: More Than Just Another Effector Pathway
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Salo‐Ahen, O. M. H., Alanko, I., Bhadane, R. N., Bonvin, A. M. J. J., Honorato, R. V., Hossain, S., Juffer, A. H., Kabedev, A., Lahtela-Kakkonen, M. K., Larsen, A. S., et al. (2020) · Processes · doi:10.3390/pr9010071 · Cited by 732
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Ostrem, J. M. L., & Shokat, K. M. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.139 · Cited by 641
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Lu, S., Jang, H., Muratcioglu, S., Gursoy, A., Keskin, O., Nussinov, R., & Zhang, J. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00542 · Cited by 355
Self-citationInhibition of RAS function through targeting an allosteric regulatory site
Spencer-Smith, R., Koide, A., Zhou, Y., Eguchi, R. R., Sha, F., Gajwani, P., Santana, D., Gupta, A., Jacobs, M., Herrero-Garcia, E., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2231 · Cited by 283
Metadata
- 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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