GTP-Dependent K-Ras Dimerization

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

来源：Structure, 2015, 23(7): 1325-1335.

DOI：10.1016/j.str.2015.04.019

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 beta-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.

• 出版日期2015-7-7