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  • Title: High-Affinity Interaction of the K-Ras4B Hypervariable Region with the Ras Active Site.
    Author: Chavan TS, Jang H, Khavrutskii L, Abraham SJ, Banerjee A, Freed BC, Johannessen L, Tarasov SG, Gaponenko V, Nussinov R, Tarasova NI.
    Journal: Biophys J; 2015 Dec 15; 109(12):2602-2613. PubMed ID: 26682817.
    Abstract:
    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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