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.
|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|
|URL link to publisher's version||http://www.nature.com/emboj/journal/v31/n11/pdf/emboj2012100a.pdf|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11533|