|Entry||Database: EMDB / ID: EMD-20551|
|Title||Structure of a MAPK pathway complex|
|Sample||ERK pathway complexMAPK/ERK pathway:|
Serine/threonine-protein kinase B-raf / 14-3-3 protein zeta/delta
|Function / homology|
Function and homology information
regulation of synapse maturation / synaptic target recognition / Golgi reassembly / respiratory system process / establishment of Golgi localization / tube formation / dUTP catabolic process / dUMP biosynthetic process / dUTP diphosphatase / dUTP diphosphatase activity ...regulation of synapse maturation / synaptic target recognition / Golgi reassembly / respiratory system process / establishment of Golgi localization / tube formation / dUTP catabolic process / dUMP biosynthetic process / dUTP diphosphatase / dUTP diphosphatase activity / protein targeting / ERK1 and ERK2 cascade / positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway / regulation of ERK1 and ERK2 cascade / hippocampal mossy fiber to CA3 synapse / lung development / melanosome / regulation of mRNA stability / platelet activation / membrane organization / ion channel binding / angiogenesis / vesicle / blood microparticle / cadherin binding / glutamatergic synapse / protein domain specific binding / transcription factor binding / cytokine-mediated signaling pathway / focal adhesion / ubiquitin protein ligase binding / protein phosphorylation / protein kinase binding / negative regulation of apoptotic process / signal transduction / magnesium ion binding / mitochondrion / RNA binding / extracellular space / extracellular exosome / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Deoxyuridine triphosphate nucleotidohydrolase / 14-3-3 domain superfamily / dUTPase-like superfamily / dUTPase, trimeric / dUTPase-like / 14-3-3 domain / 14-3-3 protein, conserved site / 14-3-3 protein
Deoxyuridine 5'-triphosphate nucleotidohydrolase / 14-3-3 protein zeta/delta
|Biological species||Homo sapiens (human) / Human (human)|
|Method||single particle reconstruction / cryo EM / Resolution: 6.8 Å|
|Authors||Park E / Rawson S / Jeon H / Eck MJ|
|Funding support|| United States, 2 items |
|Citation||Journal: Nature / Year: 2019|
Title: Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes.
Authors: Eunyoung 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 /
Abstract: 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 ...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.
|Validation Report||PDB-ID: 6q0k|
SummaryFull reportAbout validation report
|Structure viewer||EM map: |
Downloads & links
|File||Download / File: emd_20551.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)|
|Projections & slices|
Images are generated by Spider.
|Voxel size||X=Y=Z: 0.85 Å|
|Symmetry||Space group: 1|
CCP4 map header:
-Entire ERK pathway complex
|Entire||Name: ERK pathway complexMAPK/ERK pathway / Number of components: 3|
-Component #1: protein, ERK pathway complex
|Protein||Name: ERK pathway complexMAPK/ERK pathway / Recombinant expression: No|
|Mass||Experimental: 233 MDa|
|Source||Species: Homo sapiens (human)|
-Component #2: protein, Serine/threonine-protein kinase B-raf
|Protein||Name: Serine/threonine-protein kinase B-raf / Number of Copies: 2 / Recombinant expression: No|
|Mass||Theoretical: 89.322812 kDa|
|Source||Species: Homo sapiens (human)|
|Source (engineered)||Expression System: Homo sapiens (human)|
-Component #3: protein, 14-3-3 protein zeta/delta
|Protein||Name: 14-3-3 protein zeta/delta / Number of Copies: 2 / Recombinant expression: No|
|Mass||Theoretical: 27.777092 kDa|
|Source||Species: Human (human)|
|Specimen||Specimen state: Particle / Method: cryo EM|
|Sample solution||pH: 7.5|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Imaging||Microscope: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 60 e/Å2 / Illumination mode: OTHER|
|Lens||Imaging mode: OTHER|
|Specimen Holder||Model: OTHER|
|Processing||Method: single particle reconstruction / Number of projections: 66215|
|3D reconstruction||Resolution: 6.8 Å / Resolution method: FSC 0.143 CUT-OFF|
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