Architecture of autoinhibited and active BRAF–MEK1–14-3-3 complexes

Eunyoung Park, Shaun Rawson, Kunhua Li, Byeong-Won Kim, Scott B. Ficarro, Gonzalo Gonzalez-Del Pino, Humayun Sharif, Jarrod A. Marto, Hyesung Jeon () and Michael J. Eck ()
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Eunyoung Park: Dana-Farber Cancer Institute
Shaun Rawson: Harvard Medical School
Kunhua Li: Dana-Farber Cancer Institute
Byeong-Won Kim: Dana-Farber Cancer Institute
Scott B. Ficarro: Dana-Farber Cancer Institute
Gonzalo Gonzalez-Del Pino: Dana-Farber Cancer Institute
Humayun Sharif: Dana-Farber Cancer Institute
Jarrod A. Marto: Dana-Farber Cancer Institute
Hyesung Jeon: Dana-Farber Cancer Institute
Michael J. Eck: Dana-Farber Cancer Institute

Nature, 2019, vol. 575, issue 7783, 545-550

Abstract: Abstract RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival1–3. RAF activity is tightly regulated and inappropriate activation is a frequent cause of cancer4–6; however, the structural basis for RAF regulation is poorly understood at present. Here we use cryo-electron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer. The reconstruction reveals an inactive BRAF–MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of two BRAFs, which drives the formation of an active, back-to-back BRAF dimer. Our structural snapshots provide a foundation for understanding normal RAF regulation and its mutational disruption in cancer and developmental syndromes.

Date: 2019
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DOI: 10.1038/s41586-019-1660-y

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