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Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling.

Authors :
Haling JR
Sudhamsu J
Yen I
Sideris S
Sandoval W
Phung W
Bravo BJ
Giannetti AM
Peck A
Masselot A
Morales T
Smith D
Brandhuber BJ
Hymowitz SG
Malek S
Source :
Cancer cell [Cancer Cell] 2014 Sep 08; Vol. 26 (3), pp. 402-413. Date of Electronic Publication: 2014 Aug 21.
Publication Year :
2014

Abstract

Numerous oncogenic mutations occur within the BRAF kinase domain (BRAF(KD)). Here we show that stable BRAF-MEK1 complexes are enriched in BRAF(WT) and KRAS mutant (MT) cells but not in BRAF(MT) cells. The crystal structure of the BRAF(KD) in a complex with MEK1 reveals a face-to-face dimer sensitive to MEK1 phosphorylation but insensitive to BRAF dimerization. Structure-guided studies reveal that oncogenic BRAF mutations function by bypassing the requirement for BRAF dimerization for activity or weakening the interaction with MEK1. Finally, we show that conformation-specific BRAF inhibitors can sequester a dormant BRAF-MEK1 complex resulting in pathway inhibition. Taken together, these findings reveal a regulatory role for BRAF in the MAPK pathway independent of its kinase activity but dependent on interaction with MEK.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1878-3686
Volume :
26
Issue :
3
Database :
MEDLINE
Journal :
Cancer cell
Publication Type :
Academic Journal
Accession number :
25155755
Full Text :
https://doi.org/10.1016/j.ccr.2014.07.007