title: Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling.
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.
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Haling
authors.affiliation: Department of Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jawahar
authors.initials: J
authors.lastname: Sudhamsu
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.affiliation: Department of Protein Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Sandoval
authors.affiliation: Department of Protein Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Wilson
authors.initials: W
authors.lastname: Phung
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Bravo
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Giannetti
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ariana
authors.initials: A
authors.lastname: Peck
authors.affiliation: Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Masselot
authors.affiliation: Department of Structural Biology, Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Morales
authors.affiliation: Department of Structural Biology, Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
authors.forename: Darin
authors.initials: D
authors.lastname: Smith
authors.affiliation: Department of Structural Biology, Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brandhuber
authors.affiliation: Department of Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: hymowitz.sarah@gene.com.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Hymowitz
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: malek.shiva@gene.com.
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D020125:Mutation, Missense; D017354:Point Mutation; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins