BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS

BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS
Title:
BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS
Other Titles:
Science Advances
Keywords:
Publication Date:
14 August 2019
Citation:
R. Röck, J. E. Mayrhofer, O. Torres-Quesada, F. Enzler, A. Raffeiner, P. Raffeiner, A. Feichtner, R. G. Huber, S. Koide, S. S. Taylor, J. Troppmair, E. Stefan, BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS. Sci. Adv. 5, eaav8463 (2019)
Abstract:
Oncogenic BRAF mutations initiate tumor formation by unleashing the autoinhibited kinase conformation and promoting RAS-decoupled proliferative RAF-MEK-ERK signaling. We have engineered luciferase-based biosensors to systematically track full-length BRAF conformations and interactions affected by tumorigenic kinase mutations and GTP loading of RAS. Binding of structurally diverse αC-helix-OUT BRAF inhibitors (BRAFi) showed differences in specificity and efficacy by shifting patient mutation–containing BRAF reporters from the definitive opened to more closed conformations. Unexpectedly, BRAFi engagement with the catalytic pocket of V600E-mutated BRAF stabilized an intermediate and inactive kinase conformation that enhanced binary RAS:RAF interactions, also independently of RAF dimerization in melanoma cells. We present evidence that the interference with RAS interactions and nanoclustering antagonizes the sequential formation of drug-induced RAS:RAF tetramers. This suggests a previously unappreciated allosteric effect of anticancer drug-driven intramolecular communication between the kinase and RAS-binding domains of mutated BRAF, which may further promote paradoxical kinase activation and drug resistance mechanisms.
License type:
http://creativecommons.org/licenses/by-nc/4.0/
Funding Info:
This work was supported by grants from the Austrian Science Fund (FWF;P22608, P27606, P30441, to E.S. and SFB-F44) and the U.S. NIH (grant R01 CA212608 to S.K. and grant DK54441 to S.S.T.).
Description:
ISSN:
2375-2548
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