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- EMDB-20550: Structure of a MAPK pathway complex -

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Entry
Database: EMDB / ID: EMD-20550
TitleStructure of a MAPK pathway complex
Map dataStructure of a MAPK pathway complex
Sample
  • Complex: ERK pathway complex
    • Protein or peptide: Serine/threonine-protein kinase B-raf
    • Protein or peptide: Dual specificity mitogen-activated protein kinase kinase 1
    • Protein or peptide: 14-3-3 protein zeta
  • Ligand: MAGNESIUM ION
  • Ligand: 5-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide
  • Ligand: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER
KeywordsTRANSFERASE / Transferase-PROTEIN BINDING complex
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development / MAP-kinase scaffold activity ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development / MAP-kinase scaffold activity / type B pancreatic cell proliferation / Signalling to p38 via RIT and RIN / cerebellar cortex formation / head morphogenesis / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / Signaling by MAP2K mutants / negative regulation of fibroblast migration / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / regulation of Golgi inheritance / spindle pole body / mitogen-activated protein kinase kinase binding / regulation of T cell differentiation / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / positive regulation of axonogenesis / regulation of stress-activated MAPK cascade / Frs2-mediated activation / stress fiber assembly / ERBB2-ERBB3 signaling pathway / protein kinase activator activity / positive regulation of axon regeneration / MAPK3 (ERK1) activation / endodermal cell differentiation / face development / MAP kinase kinase activity / synaptic vesicle exocytosis / Bergmann glial cell differentiation / somatic stem cell population maintenance / thyroid gland development / Uptake and function of anthrax toxins / MAP kinase kinase kinase activity / negative regulation of endothelial cell apoptotic process / Schwann cell development / positive regulation of substrate adhesion-dependent cell spreading / keratinocyte differentiation / positive regulation of stress fiber assembly / response to cAMP / protein serine/threonine/tyrosine kinase activity / myelination / ERK1 and ERK2 cascade / cellular response to calcium ion / substrate adhesion-dependent cell spreading / protein serine/threonine kinase activator activity / insulin-like growth factor receptor signaling pathway / MAP3K8 (TPL2)-dependent MAPK1/3 activation / cellular response to nerve growth factor stimulus / thymus development / Signal transduction by L1 / cell motility / animal organ morphogenesis / long-term synaptic potentiation / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / epidermal growth factor receptor signaling pathway / visual learning / positive regulation of protein serine/threonine kinase activity / neuron differentiation / 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 / chemotaxis / cellular senescence / MAPK cascade / Signaling by BRAF and RAF1 fusions / cellular response to xenobiotic stimulus / late endosome / positive regulation of peptidyl-serine phosphorylation / presynapse / heart development / T cell receptor signaling pathway / regulation of cell population proliferation / T cell differentiation in thymus / cell body / scaffold protein binding / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / early endosome / non-specific serine/threonine protein kinase
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. ...: / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / 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 / Dual specificity mitogen-activated protein kinase kinase 1 / 14-3-3 protein zeta
Similarity search - Component
Biological speciesHomo sapiens (human) / Spodoptera exigua (beet armyworm)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.9 Å
AuthorsPark E / Rawson S
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) releaseSep 18, 2019-
Map releaseOct 9, 2019-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0285
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0285
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6q0j
  • Surface level: 0.0285
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20550.png

Downloads & links

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Map

FileDownload / File: emd_20550.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of a MAPK pathway complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.11 Å/pix.
x 256 pix.
= 284.16 Å		1.11 Å/pix.
x 256 pix.
= 284.16 Å		1.11 Å/pix.
x 256 pix.
= 284.16 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.11 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0285 / Movie #1: 0.0285
Minimum - Maximum-0.058593486 - 0.12538469
Average (Standard dev.)0.000011677979 (±0.0031931626)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 284.16 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.111.111.11
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z284.160284.160284.160
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0590.1250.000

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Supplemental data

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Sample components

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Entire : ERK pathway complex

EntireName: ERK pathway complex
Components
  • Complex: ERK pathway complex
    • Protein or peptide: Serine/threonine-protein kinase B-raf
    • Protein or peptide: Dual specificity mitogen-activated protein kinase kinase 1
    • Protein or peptide: 14-3-3 protein zeta
  • Ligand: MAGNESIUM ION
  • Ligand: 5-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide
  • Ligand: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER

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Supramolecule #1: ERK pathway complex

SupramoleculeName: ERK pathway complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: insect cell endogenous 14-3-3 co-purified with human BRAF and MEK
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 325 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: 89.306812 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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 RDRSSAAPNV 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

UniProtKB: Serine/threonine-protein kinase B-raf

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Macromolecule #2: Dual specificity mitogen-activated protein kinase kinase 1

MacromoleculeName: Dual specificity mitogen-activated protein kinase kinase 1
type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: mitogen-activated protein kinase kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.934543 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSSHHHHHH SAVDENLYFQ GGMPKKKPTP IQLNPAPDGS AVNGTSSAET NLEALQKKLE ELELDEQQRK RLEAFLTQKQ KVGELKDDD FEKISELGAG NGGVVFKVSH KPSGLVMARK LIHLEIKPAI RNQIIRELQV LHECNSPYIV GFYGAFYSDG E ISICMEHM ...String:
MGSSHHHHHH SAVDENLYFQ GGMPKKKPTP IQLNPAPDGS AVNGTSSAET NLEALQKKLE ELELDEQQRK RLEAFLTQKQ KVGELKDDD FEKISELGAG NGGVVFKVSH KPSGLVMARK LIHLEIKPAI RNQIIRELQV LHECNSPYIV GFYGAFYSDG E ISICMEHM DGGSLDQVLK KAGRIPEQIL GKVSIAVIKG LTYLREKHKI MHRDVKPSNI LVNSRGEIKL CDFGVSGQLI DA MANAFVG TRSYMSPERL QGTHYSVQSD IWSMGLSLVE MAVGRYPIPP PDAKELELMF GCQVEGDAAE TPPRPRTPGR PLS SYGMDS RPPMAIFELL DYIVNEPPPK LPSGVFSLEF QDFVNKCLIK NPAERADLKQ LMVHAFIKRS DAEEVDFAGW LCST IGLNQ PSTPTHAAGV

UniProtKB: Dual specificity mitogen-activated protein kinase kinase 1

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Macromolecule #3: 14-3-3 protein zeta

MacromoleculeName: 14-3-3 protein zeta / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Spodoptera exigua (beet armyworm)
Molecular weightTheoretical: 28.108514 KDa
SequenceString: MSVDKEELVQ RAKLAEQAER YDDMAAAMKE VTETGVELSN EERNLLSVAY KNVVGARRSS WRVISSIEQK TEGSERKQQM AKEYRVKVE KELREICYDV LGLLDKHLIP KASNPESKVF YLKMKGDYYR YLAEVATGET RNSVVEDSQK AYQDAFEISK A KMQPTHPI ...String:
MSVDKEELVQ RAKLAEQAER YDDMAAAMKE VTETGVELSN EERNLLSVAY KNVVGARRSS WRVISSIEQK TEGSERKQQM AKEYRVKVE KELREICYDV LGLLDKHLIP KASNPESKVF YLKMKGDYYR YLAEVATGET RNSVVEDSQK AYQDAFEISK A KMQPTHPI RLGLALNFSV FYYEILNSPD KACQLAKQAF DDAIAELDTL NEDSYKDSTL IMQLLRDNLT LWTSDTQGDG DE PAEGGDN

UniProtKB: 14-3-3 protein zeta

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: 5-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)imidazo[1,5-a...

MacromoleculeName: 5-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide
type: ligand / ID: 5 / Number of copies: 2 / Formula: LCJ
Molecular weightTheoretical: 456.21 Da
Chemical component information

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

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Macromolecule #6: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / type: ligand / ID: 6 / Number of copies: 2 / Formula: AGS
Molecular weightTheoretical: 523.247 Da
Chemical component information

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

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 53.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 425135
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-6q0j:
Structure of a MAPK pathway complex

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