PMID:26051715

Citation	Muratcioglu, S, Chavan, TS, Freed, BC, Jang, H, Khavrutskii, L, Freed, RN, Dyba, MA, Stefanisko, K, Tarasov, SG, Gursoy, A, Keskin, O, Tarasova, NI, Gaponenko, V and Nussinov, R (2015) GTP-Dependent K-Ras Dimerization. Structure 23:1325-35
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.
Links	PubMed PMC4497850 Online version:10.1016/j.str.2015.04.019
Keywords	Catalytic Domain; Guanosine Triphosphate/chemistry; Humans; Kinetics; Protein Binding; Protein Interaction Domains and Motifs; Protein Multimerization; Proto-Oncogene Proteins p21(ras)/chemistry
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:RASK	enables	GO:0042802: identical protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P01116-2	F		Seeded From UniProt	complete

References

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