GTP-Dependent K-Ras Dimerization

Serena Muratcioglu, Tanmay S. Chavan, Benjamin C. Freed, Hyunbum Jang, Lyuba Khavrutskii, R. Natasha Freed, Marzena A. Dyba, Karen Stefanisko, Sergey G. Tarasov, Attila Gursoy, Ozlem Keskin, Nadya I. Tarasova, Vadim Gaponenko, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Summary Ras proteins recruit and activate effectors, including Raf, that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, activation of Raf requires its dimerization. It has been suspected that dimeric Ras may promote dimerization and activation of Raf. Here, we show that the GTP-bound catalytic domain of K-Ras4B, a highly oncogenic splice variant of the K-Ras isoform, forms stable homodimers. We observe two major dimer interfaces. The first, highly populated β-sheet dimer interface is at the Switch I and effector binding regions, overlapping the binding surfaces of Raf, PI3K, RalGDS, and additional effectors. This interface has to be inhibitory to such effectors. The second, helical interface also overlaps the binding sites of some effectors. This interface may promote activation of Raf. Our data reveal how Ras self-association can regulate effector binding and activity, and suggest that disruption of the helical dimer interface by drugs may abate Raf signaling in cancer.

Original languageEnglish
Article number3181
Pages (from-to)1325-1335
Number of pages11
JournalStructure
Volume23
Issue number7
DOIs
StatePublished - 9 Jul 2015

Funding

FundersFunder number
TUBITAK114M196
National Institutes of HealthHHSN261200800001E
American Cancer SocietyRGS-09-057-01-GMC
National Cancer InstituteR01CA135341
Frederick National Laboratory for Cancer Research

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