Journal
STRUCTURE
Volume 23, Issue 7, Pages 1325-1335Publisher
CELL PRESS
DOI: 10.1016/j.str.2015.04.019
Keywords
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Funding
- American Cancer Society [RGS-09-057-01-GMC]
- National Cancer Institute [R01 CA135341]
- Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]
- Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research
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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.
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