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Structure. 2015 Jul 7;23(7):1325-35. doi: 10.1016/j.str.2015.04.019. Epub 2015 Jun 4.

GTP-Dependent K-Ras Dimerization.

Author information

1
Department of Chemical and Biological Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
2
Department of Medicinal Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
3
Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
4
Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
5
Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Structural Biophysics Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
6
Structural Biophysics Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
7
Department of Computer Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
8
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA. Electronic address: vadimg@uic.edu.
9
Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: nussinor@helix.nih.gov.

Abstract

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.

PMID:
26051715
PMCID:
PMC4497850
DOI:
10.1016/j.str.2015.04.019
[Indexed for MEDLINE]
Free PMC Article

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