BRAF oncogenic mutants evade autoinhibition through a common mechanism

• 成果类型: Article
• 署名作者: Lavoie, Hugo; Jin, Ting; Lajoie, Driss; Decossas, Marion; Gendron, Patrick; Wang, Bing; Filandr, Frantisek; Sahmi, Malha; Jo, Chang Hwa; Weber, Sandra; Arseneault, Genevieve; Tripathy, Sasmita; Beaulieu, Pierre; Schuetz, Doris A.; Schriemer, David C.; Marinier, Anne; Rice, William J.; Maisonneuve, Pierre; Therrien, Marc
• 署名单位: Universite de Montreal; Universite de Bordeaux; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Chemistry (INC); NYU Langone Medical Center; University of Calgary; Universite de Montreal; NYU Langone Medical Center; Universite de Montreal
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9328
• DOI: 10.1126/science.adp2742
• 发表日期: 2025-05-29
• 关键词: cryo-em structure; raf inhibitors; protein-kinases; mapk pathway; b-raf; activation; mutations; egfr; RESOLUTION; accuracy

摘要

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 alpha C displacement. PLX8394, a BRAF inhibitor that stabilizes helix alpha C in an inactive conformation, restored the autoinhibited conformation of oncogenic BRAF, explaining the properties of this class of compounds.