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Distinct requirement for an intact dimer interface in wildtype, V600E and kinase-dead BRAF signaling


Signal transduction by Raf-kinases involves their dimerization, a process that underlies the paradoxical effects of Raf-inhibitors and that is also considered for novel therapeutic approaches. A central cluster within the dimer interface (DIF) of the kinase domain and 14-3-3 proteins are implicated in Raf-dimerization. However, the importance of the DIF for the signaling potential of full-length B-Raf and its oncogenic counterparts is unknown. Here, we show that the DIF plays a pivotal role for the activity of B-Raf and several of its gain-of-function mutants. In striking contrast, the most clinically relevant mutant, B-RafV600E, is highly resilient to mutations in the DIF, the C-terminal 14-3-3 binding motif, or a combination of both. Based on our findings that B-RafV600E forms stable dimers, extended protomer contacts and higher-ordered complexes, we propose that the dimerization and transforming activity of B-RafV600E stems from the concerted action of the DIF, 14-3-3 proteins and its active conformation.

Type Journal
Authors Roering, M.; Herr, R.; Fiala, G.J.; Heilmann, K.; Braun, S.; Eisenhardt, A.E.; Halbach, S.; Schamel, W.W.; Saunders, D.N.; Brummer, T.;
Publisher Name EMBO JOURNAL
Published Date 2012-04-17
Published Volume 31
Published Issue 11
Published Pages 2629-2647
Status Published in-print
DOI 10.1038/emboj.2012.100
URL link to publisher's version
OpenAccess link to author's accepted manuscript version