BRAF oncogenic mutants evade autoinhibition through a common mechanism

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.

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Publication Details

Journal
Science
Published
2025-05-29
DOI
https://doi.org/10.1126/science.adp2742
Citations
18
Primary Topic
Melanoma and MAPK Pathways
Type
article
Field-Weighted Citation Impact
14.51
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article

BRAF oncogenic mutants evade autoinhibition through a common mechanism

William J. Rice, Anne Marinier, Hugo Lavoie, Geneviève Arseneault et al.
18 citations
Science
Melanoma and MAPK Pathways
14.51
article

BRAF oncogenic mutants evade autoinhibition through a common mechanism

William J. Rice, Anne Marinier, Hugo Lavoie, Geneviève Arseneault, Driss Lajoie, Marion Décossas, Pierre Maisonneuve, Sasmita Tripathy, Doris A. Schuetz, Sandra Weber, Marc Therrien, Patrick Gendron, Chang Hwa Jo, David C. Schriemer, Pierre Beaulieu, Malha Sahmi, František Filandr, Bing Wang, Ting Jin
article en
18 citations

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.

ScienceVol. 388(6750)
Centre National de la Recherche Scientifique (FR), Université de Bordeaux (FR), University of Calgary (CA), NYU Langone Health (US), Institute for Research in Immunology and Cancer (CA), Chimie et Biologie des Membranes et des Nanoobjects (FR), Institut Européen de Chimie et Biologie (FR), Institut Polytechnique de Bordeaux (FR), Université de Montréal (CA)
Openalex Percentile: Top 1%
Melanoma and MAPK Pathways
14.51
DOIOpen Access PDFOpenAlex
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