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- EMDB-20551: Structure of a MAPK pathway complex -

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Basic information

Entry
Database: EMDB / ID: EMD-20551
TitleStructure of a MAPK pathway complex
Map dataStructure of a MAPK pathway complex
Sample
  • Complex: ERK pathway complexMAPK/ERK pathway
    • Protein or peptide: Serine/threonine-protein kinase B-raf
    • Protein or peptide: 14-3-3 protein zeta/delta
Function / homology
Function and homology information


Golgi reassembly / regulation of synapse maturation / NOTCH4 Activation and Transmission of Signal to the Nucleus / trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / establishment of Golgi localization / head morphogenesis / Signalling to p38 via RIT and RIN ...Golgi reassembly / regulation of synapse maturation / NOTCH4 Activation and Transmission of Signal to the Nucleus / trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / establishment of Golgi localization / head morphogenesis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / ARMS-mediated activation / endothelial cell apoptotic process / Rap1 signalling / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / negative regulation of protein localization to nucleus / mitogen-activated protein kinase kinase binding / Negative feedback regulation of MAPK pathway / regulation of T cell differentiation / KSRP (KHSRP) binds and destabilizes mRNA / GP1b-IX-V activation signalling / positive regulation of axonogenesis / Frs2-mediated activation / stress fiber assembly / positive regulation of axon regeneration / face development / synaptic vesicle exocytosis / somatic stem cell population maintenance / MAP kinase kinase activity / thyroid gland development / Regulation of localization of FOXO transcription factors / Interleukin-3, Interleukin-5 and GM-CSF signaling / MAP kinase kinase kinase activity / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / cellular response to glucose starvation / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / response to cAMP / negative regulation of TORC1 signaling / positive regulation of stress fiber assembly / ERK1 and ERK2 cascade / cellular response to calcium ion / negative regulation of innate immune response / substrate adhesion-dependent cell spreading / protein sequestering activity / cellular response to nerve growth factor stimulus / regulation of ERK1 and ERK2 cascade / thymus development / long-term synaptic potentiation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / Deactivation of the beta-catenin transactivating complex / TP53 Regulates Metabolic Genes / Negative regulation of NOTCH4 signaling / animal organ morphogenesis / Spry regulation of FGF signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / visual learning / MAP2K and MAPK activation / epidermal growth factor receptor signaling pathway / response to peptide hormone / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / MAPK cascade / melanosome / Signaling by BRAF and RAF1 fusions / cellular response to xenobiotic stimulus / presynapse / positive regulation of peptidyl-serine phosphorylation / cell body / T cell differentiation in thymus / regulation of cell population proliferation / T cell receptor signaling pathway / scaffold protein binding / blood microparticle / DNA-binding transcription factor binding / negative regulation of neuron apoptotic process / vesicle / transmembrane transporter binding / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / neuron projection / protein kinase activity / cadherin binding / protein phosphorylation / focal adhesion / intracellular membrane-bounded organelle / protein serine kinase activity
Similarity search - Function
Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain ...Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain / 14-3-3 domain superfamily / 14-3-3 protein / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Serine/threonine-protein kinase B-raf / 14-3-3 protein zeta/delta
Similarity search - Component
Biological speciesHomo sapiens (human) / Human (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.8 Å
AuthorsPark E / Rawson S / Jeon H / Eck MJ
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)P50CA165962 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R50CA221830 United States
CitationJournal: 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.
History
DepositionAug 1, 2019-
Header (metadata) releaseOct 2, 2019-
Map releaseOct 9, 2019-
UpdateApr 22, 2020-
Current statusApr 22, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6q0k
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20551.png

Downloads & links

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Map

FileDownload / File: emd_20551.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of a MAPK pathway complex
Voxel sizeX=Y=Z: 0.85 Å
Density
Contour LevelBy AUTHOR: 0.021 / Movie #1: 0.021
Minimum - Maximum-0.037883114 - 0.12774667
Average (Standard dev.)0.00048250504 (±0.004253514)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.850.850.85
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z217.600217.600217.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0380.1280.000

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Supplemental data

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Sample components

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Entire : ERK pathway complex

EntireName: ERK pathway complexMAPK/ERK pathway
Components
  • Complex: ERK pathway complexMAPK/ERK pathway
    • Protein or peptide: Serine/threonine-protein kinase B-raf
    • Protein or peptide: 14-3-3 protein zeta/delta

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Supramolecule #1: ERK pathway complex

SupramoleculeName: ERK pathway complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightExperimental: 233 kDa/nm

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Macromolecule #1: Serine/threonine-protein kinase B-raf

MacromoleculeName: Serine/threonine-protein kinase B-raf / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 89.322812 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSYYHHHHHH HHDIPTTENL YFQGAMDMAA LSGGGGGGAE PGQALFNGDM EPEAGAGAGA AASSAADPAI PEEVWNIKQM IKLTQEHIE ALLDKFGGEH NPPSIYLEAY EEYTSKLDAL QQREQQLLES LGNGTDFSVS SSASMDTVTS SSSSSLSVLP S SLSVFQNP ...String:
MSYYHHHHHH HHDIPTTENL YFQGAMDMAA LSGGGGGGAE PGQALFNGDM EPEAGAGAGA AASSAADPAI PEEVWNIKQM IKLTQEHIE ALLDKFGGEH NPPSIYLEAY EEYTSKLDAL QQREQQLLES LGNGTDFSVS SSASMDTVTS SSSSSLSVLP S SLSVFQNP TDVARSNPKS PQKPIVRVFL PNKQRTVVPA RCGVTVRDSL KKALMMRGLI PECCAVYRIQ DGEKKPIGWD TD ISWLTGE ELHVEVLENV PLTTHNFVRK TFFTLAFCDF CRKLLFQGFR CQTCGYKFHQ RCSTEVPLMC VNYDQLDLLF VSK FFEHHP IPQEEASLAE TALTSGSSPS APASDSIGPQ ILTSPSPSKS IPIPQPFRPA DEDHRNQFGQ RDRSSSAPNV HINT IEPVN IDDLIRDQGF RGDGGSTTGL SATPPASLPG SLTNVKALQK SPGPQRERKS SSSSEDRNRM KTLGRRDSSD DWEIP DGQI TVGQRIGSGS FGTVYKGKWH GDVAVKMLNV TAPTPQQLQA FKNEVGVLRK TRHVNILLFM GYSTKPQLAI VTQWCE GSS LYHHLHIIET KFEMIKLIDI ARQTAQGMDY LHAKSIIHRD LKSNNIFLHE DLTVKIGDFG LATVKSRWSG SHQFEQL SG SILWMAPEVI RMQDKNPYSF QSDVYAFGIV LYELMTGQLP YSNINNRDQI IFMVGRGYLS PDLSKVRSNC PKAMKRLM A ECLKKKRDER PLFPQILASI ELLARSLPKI HRSA(SEP)EPSLN RAGFQTEDFS LYACASPKTP IQAGGYGAFP VHGTS AWSH PQFEK

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Macromolecule #2: 14-3-3 protein zeta/delta

MacromoleculeName: 14-3-3 protein zeta/delta / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Human (human)
Molecular weightTheoretical: 27.777092 KDa
SequenceString: MDKNELVQKA KLAEQAERYD DMAACMKSVT EQGAELSNEE RNLLSVAYKN VVGARRSSWR VVSSIEQKTE GAEKKQQMAR EYREKIETE LRDICNDVLS LLEKFLIPNA SQAESKVFYL KMKGDYYRYL AEVAAGDDKK GIVDQSQQAY QEAFEISKKE M QPTHPIRL ...String:
MDKNELVQKA KLAEQAERYD DMAACMKSVT EQGAELSNEE RNLLSVAYKN VVGARRSSWR VVSSIEQKTE GAEKKQQMAR EYREKIETE LRDICNDVLS LLEKFLIPNA SQAESKVFYL KMKGDYYRYL AEVAAGDDKK GIVDQSQQAY QEAFEISKKE M QPTHPIRL GLALNFSVFY YEILNSPEKA CSLAKTAFDE AIAELDTLSE ESYKDSTLIM QLLRDNLTLW TSDTQGDEAE AG EGGEN

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 66215

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Atomic model buiding 1

Initial model
PDB IDChain

4mne

chain_id: A

4mne

chain_id: B

3nkx

chain_id: X

3nkx

chain_id: Y
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-6q0k:
Structure of a MAPK pathway complex

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