Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling

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Abstract

Numerous oncogenic mutations occur within the BRAF kinase domain (BRAFKD). Here we show that stable BRAF-MEK1 complexes are enriched in BRAFWT and KRAS mutant (MT) cells but not in BRAFMT cells. The crystal structure of the BRAFKD 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.

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Haling, J. R., Sudhamsu, J., Yen, I., Sideris, S., Sandoval, W., Phung, W., … Malek, S. (2014). Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling. Cancer Cell, 26(3), 402–413. https://doi.org/10.1016/j.ccr.2014.07.007

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