High-Affinity Interaction of the K-Ras4B Hypervariable Region with the Ras Active Site

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)2602-2613
Number of pages12
JournalBiophysical Journal
Issue number12
StatePublished - 15 Dec 2015


FundersFunder number
National Institutes of Health
National Heart, Lung, and Blood InstituteR21HL118588
National Cancer InstituteZIABC011306, R01CA135341, R01CA188427
National Institute of Allergy and Infectious DiseasesR01AI058072
Frederick National Laboratory for Cancer Research


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