BRAF oncogenic mutants evade autoinhibition through a common mechanism
Hugo Lavoie, Ting Jin, Driss Lajoie, Marion Décossas, Patrick Gendron, Bing Wang, František Filandr, Malha Sahmi, Chang Hwa Jo, Sandra Weber, Geneviève Arseneault, Sasmita Tripathy, Pierre Beaulieu, Doris A. Schuetz, David C. Schriemer, Anne Marinier, William J. Rice, Pierre Maisonneuve, Marc Therrien
Abstract
Uncontrolled activation of the rat sarcoma (RAS)-extracellular signal-regulated kinase (ERK) pathway drives tumor growth, often because of oncogenic BRAF mutations. BRAF regulation, involving monomeric autoinhibition and activation by dimerization, has been intensely scrutinized, but mechanisms enabling oncogenic mutants to evade regulation remain unclear. By using cryo-electron microscopy, we solved the three-dimensional structures of the three oncogenic BRAF mutant classes, including the common V600E variant. These mutations disrupted wild-type BRAF's autoinhibited state, mediated by interactions between the cysteine-rich domain and kinase domain, thereby shifting the kinase domain into a preactivated conformation. This structural change likely results from helix αC displacement. PLX8394, a BRAF inhibitor that stabilizes helix αC in an inactive conformation, restored the autoinhibited conformation of oncogenic BRAF, explaining the properties of this class of compounds.