Journal
BIOPHYSICAL JOURNAL
Volume 109, Issue 12, Pages 2602-2613Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2015.09.034
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Funding
- National Cancer Institute [R01CA135341, R01CA188427]
- National Heart, Lung, and Blood Institute [R21HL118588]
- National Institute of Allergy and Infectious Diseases [R01AI058072]
- Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]
- Intramural Research Program of the National Institutes of Health, Frederick National Lab, Center for Cancer Research
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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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