High-affinity interaction of the K-Ras4B hypervariable region with the RAS active site
Open accessAbstract
Ras proteins are small GTPases that act as signal transducers between cell surface receptors and several intracellular signaling cascades. They contain highly homologous catalytic domains and flexible C-terminal hypervariable regions (HVRs) that differ across Ras isoforms. KRAS is among the most frequently mutated oncogenes in human tumors. Surprisingly, we found that the C-terminal HVR of K-Ras4B, thought to minimally impact the catalytic domain, directly interacts with the active site of the protein. The interaction is almost 100-fold tighter with the GDP-bound than the GTP-bound protein. HVR binding interferes with Ras-Raf interaction, modulates binding to phospholipids, and slightly slows down nucleotide exchange. The data indicate that contrary to previously suggested models of K-Ras4B signaling, HVR plays essential roles in regulation of signaling. High affinity binding of short peptide analogs of HVR to K-Ras active site suggests that targeting this surface with inhibitory synthetic molecules for the therapy of KRAS-dependent tumors is feasible.
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Previous molecular dynamics simulation studies of KRAS at microsecond timescales had total simulation times in the range of 1-8 μs, which is likely not sufficient to unravel long-time dynamics associated with slow conformational changes.
“The total simulation times of these studies were in the range of 1–8 μs, which is reasonable but likely not sufficient to unravel long-time dynamics associated with slow conformational changes.”
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References 57 · Cited by 79
- Authors
- Chavan, T. S., Jang, H., Khavrutskii, L., Abraham, S. J., Banerjee, A., Freed, B. C., Johannessen, L., Tarasov, S. G., Gaponenko, V., Nussinov, R., & Tarasova, N. I.
- Affiliations
- University of Illinois Chicago (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Tel Aviv University (IL)
- National Institutes of Health (US)
- Corresponding author
- Gaponenko, Vadim
- Nussinov, Ruth
- Tarasova, Nadya I.
- ORCID
- Venue
- Biophysical Journal
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 109
- Issue
- 12
- Pages
- 2602-2613
- ISSN
- 0006-3495 (ISSN-L)
- PMC
- PMC4699860
- OpenAlex
- W2210900834
- Cited by
- 79
- References
- 57
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 6 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 8 · 2019: 10 · 2018: 8 · 2017: 14 · 2016: 6 · 2015: 6
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biophysical Journal (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- Frederick National Laboratory for Cancer Research
- National Institutes of Health (HHSN261200800001C)
- National Heart, Lung, and Blood Institute (R21HL118588)
- National Cancer Institute (R01CA188427, HHSN261200800001E), R01CA135341)
- National Institute of Allergy and Infectious Diseases (R01AI058072)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- K-Ras4B, Ras-Raf interaction, GTP-bound Ras, phospholipid binding, nucleotide exchange, KRAS inhibitors
- MeSH terms
- Amino Acid Sequence, Guanosine Diphosphate, Guanosine Triphosphate, Molecular Sequence Data, Peptide Fragments, Protein Binding, Proto-Oncogene Proteins p21(ras), ras Proteins, Catalytic Domain, Biocatalysis, Molecular Dynamics Simulation
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