Cryo-EM structure of a RAS/RAF recruitment complex

Eunyoung Park, Shaun Rawson, Anna Schmoker, Byeong-Won Kim, Sehee Oh, Kangkang Song, Hyesung Jeon () and Michael J. Eck ()
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Eunyoung Park: Dana-Farber Cancer Institute
Shaun Rawson: Harvard Medical School
Anna Schmoker: Dana-Farber Cancer Institute
Byeong-Won Kim: Dana-Farber Cancer Institute
Sehee Oh: Dana-Farber Cancer Institute
Kangkang Song: University of Massachusetts Chan Medical School
Hyesung Jeon: Dana-Farber Cancer Institute
Michael J. Eck: Dana-Farber Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract RAF-family kinases are activated by recruitment to the plasma membrane by GTP-bound RAS, whereupon they initiate signaling through the MAP kinase cascade. Prior structural studies of KRAS with RAF have focused on the isolated RAS-binding and cysteine-rich domains of RAF (RBD and CRD, respectively), which interact directly with RAS. Here we describe cryo-EM structures of a KRAS bound to intact BRAF in an autoinhibited state with MEK1 and a 14-3-3 dimer. Analysis of this KRAS/BRAF/MEK1/14-3-3 complex reveals KRAS bound to the RAS-binding domain of BRAF, captured in two orientations. Core autoinhibitory interactions in the complex are unperturbed by binding of KRAS and in vitro activation studies confirm that KRAS binding is insufficient to activate BRAF, absent membrane recruitment. These structures illustrate the separability of binding and activation of BRAF by RAS and suggest stabilization of this pre-activation intermediate as an alternative therapeutic strategy to blocking binding of KRAS.

Date: 2023
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DOI: 10.1038/s41467-023-40299-6

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