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Structure paper

TitleArchitecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes.
Journal, issue, pagesNature, Vol. 575, Issue 7783, Page 545-550, Year 2019
Publish dateOct 3, 2019
AuthorsEunyoung Park / Shaun Rawson / Kunhua Li / Byeong-Won Kim / Scott B Ficarro / Gonzalo Gonzalez-Del Pino / Humayun Sharif / Jarrod A Marto / Hyesung Jeon / Michael J Eck /
PubMed AbstractRAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly ...RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly regulated and inappropriate activation is a frequent cause of cancer; 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.
External linksPubMed:31581174 / Publisher's page
Keywords14-3-3 Proteins / BRAF protein, human / Binding Sites / Cell Transformation, Neoplastic / Cryoelectron Microscopy / Humans / MAP Kinase Kinase 1 / MAP2K1 protein, human / Models, Molecular / Mutation / Phosphorylation / Protein Binding / Protein Domains / Protein Multimerization / Proto-Oncogene Proteins B-raf / TRANSFERASE / BRAF / MEK1 / Transferase/PROTEIN BINDING / Transferase-PROTEIN BINDING complex / SIGNALING PROTEIN/Transferase / SIGNALING PROTEIN-Transferase complex
MethodsEM (single particle) / X-ray diffraction
Resolution2.59 - 6.8 A
Structure data

EMDB-0541:
Structure of a MAPK pathway complex

EMDB-20550:
Structure of a MAPK pathway complex

EMDB-20551:
Structure of a MAPK pathway complex

EMDB-20552:
Structure of a MAPK pathway complex

PDB-6nyb:
Structure of a MAPK pathway complex

PDB-6pp9:
Crystal structure of BRAF:MEK1 complex

PDB-6q0j:
Structure of a MAPK pathway complex

PDB-6q0k:
Structure of a MAPK pathway complex

PDB-6q0t:
Structure of a MAPK pathway complex

Chemicals

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-ZN:
ZINC ION / Zinc

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

ChemComp-MG:
MAGNESIUM ION / Magnesium

ChemComp-LCJ:
5-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-CL:
CHLORIDE ION / Chloride

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • Beet armyworm (beet armyworm)
  • Human (human)
  • spodoptera exigua (beet armyworm)

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