Tanmay S. Chavan, Hyunbum Jang, Lyuba Khavrutskii, Sherwin J. Abraham, Avik Banerjee, Benjamin C. Freed, Liv Johannessen, Sergey G. Tarasov, Vadim Gaponenko, Ruth Nussinov, Nadya I. Tarasova
2015 vol: 109 issue: 12 pp: 2602-2613 doi: 10.1016/j.bpj.2015.09.034
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.
Topics: Nanodiscs, NMR, Peptides, Monolith – MicroScale Thermophoresis, MST, Proteins, Publications