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- EMDB-15233: Structure of the MAPK p38alpha in complex with its activating MAP... -

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Entry
Database: EMDB / ID: EMD-15233
TitleStructure of the MAPK p38alpha in complex with its activating MAP2K MKK6
Map dataunsharpened map
Sample
  • Complex: Complex between the MAP2K MKK6 and its substrate MAPK p38alpha
    • Complex: Mitogen-activated protein kinase 14 (MAPK p38alpha)
      • Protein or peptide: Mitogen-activated protein kinase 14
    • Complex: Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K MKK6)
      • Protein or peptide: Dual specificity mitogen-activated protein kinase kinase 6
  • Ligand: PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER
  • Ligand: MAGNESIUM ION
KeywordsKinase / Signalling / MAP kinase / phosphoryl transfer / IMMUNE SYSTEM
Function / homology
Function and homology information


cellular response to sorbitol / ovulation cycle process / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / mitogen-activated protein kinase kinase / positive regulation of prostaglandin secretion / stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / negative regulation of cold-induced thermogenesis / CD163 mediating an anti-inflammatory response ...cellular response to sorbitol / ovulation cycle process / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / mitogen-activated protein kinase kinase / positive regulation of prostaglandin secretion / stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / negative regulation of cold-induced thermogenesis / CD163 mediating an anti-inflammatory response / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / cartilage condensation / positive regulation of myoblast fusion / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / D-glucose import / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / p38MAPK cascade / PI5P Regulates TP53 Acetylation / : / Regulation of MITF-M-dependent genes involved in pigmentation / fatty acid oxidation / MAP kinase kinase activity / cellular response to lipoteichoic acid / response to muramyl dipeptide / response to dietary excess / Uptake and function of anthrax toxins / MAP kinase activity / RHO GTPases Activate NADPH Oxidases / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / mitogen-activated protein kinase / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / positive regulation of cardiac muscle cell proliferation / cardiac muscle contraction / lipopolysaccharide-mediated signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / positive regulation of brown fat cell differentiation / positive regulation of erythrocyte differentiation / osteoclast differentiation / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / response to ischemia / activated TAK1 mediates p38 MAPK activation / positive regulation of D-glucose import / stem cell differentiation / cellular response to ionizing radiation / negative regulation of inflammatory response to antigenic stimulus / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / placenta development / PKR-mediated signaling / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / Interleukin-1 signaling / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / chemotaxis / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / cellular senescence / MAPK cascade / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / protein tyrosine kinase activity / cellular response to lipopolysaccharide / protein phosphatase binding / angiogenesis / secretory granule lumen / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / transcription by RNA polymerase II / positive regulation of MAPK cascade
Similarity search - Function
Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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 ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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
Dual specificity mitogen-activated protein kinase kinase 6 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsBowler MW / Juyoux P / Pellegrini E
Funding support1 items
OrganizationGrant numberCountry
Not funded
Citation
Journal: Science / Year: 2023
Title: Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation.
Authors: Pauline Juyoux / Ioannis Galdadas / Dorothea Gobbo / Jill von Velsen / Martin Pelosse / Mark Tully / Oscar Vadas / Francesco Luigi Gervasio / Erika Pellegrini / Matthew W Bowler /
Abstract: The mitogen-activated protein kinase (MAPK) p38α is a central component of signaling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the ...The mitogen-activated protein kinase (MAPK) p38α is a central component of signaling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the molecular mechanism of its activation by double phosphorylation from MAPK kinases (MAP2Ks), because of the challenge of trapping a transient and dynamic heterokinase complex. We applied a multidisciplinary approach to generate a structural model of p38α in complex with its MAP2K, MKK6, and to understand the activation mechanism. Integrating cryo-electron microscopy with molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and experiments in cells, we demonstrate a dynamic, multistep phosphorylation mechanism, identify catalytically relevant interactions, and show that MAP2K-disordered amino termini determine pathway specificity. Our work captures a fundamental step of cell signaling: a kinase phosphorylating its downstream target kinase.
#1: Journal: Biorxiv / Year: 2022
Title: Architecture of the MKK6-p38 alpha complex defines the basis of MAPK specificity and activation
Authors: Juyoux P / Galdadas I / Gobbo D / Tully M / Gervasio FL / Pellegrini E / Bowler MW
History
DepositionJun 23, 2022-
Header (metadata) releaseJul 13, 2022-
Map releaseJul 13, 2022-
UpdateSep 27, 2023-
Current statusSep 27, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15233.png

Downloads & links

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Map

FileDownload / File: emd_15233.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationunsharpened map
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.64 Å/pix.
x 400 pix.
= 255.2 Å		0.64 Å/pix.
x 400 pix.
= 255.2 Å		0.64 Å/pix.
x 400 pix.
= 255.2 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.638 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.018
Minimum - Maximum-0.104980186 - 0.21220645
Average (Standard dev.)-0.00024204231 (±0.004240711)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 255.20001 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_15233_msk_1.map
Projections & Slices
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Half map: half map A

Fileemd_15233_half_map_1.map
Annotationhalf map A
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Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_15233_half_map_2.map
Annotationhalf map B
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Sample components

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Entire : Complex between the MAP2K MKK6 and its substrate MAPK p38alpha

EntireName: Complex between the MAP2K MKK6 and its substrate MAPK p38alpha
Components
  • Complex: Complex between the MAP2K MKK6 and its substrate MAPK p38alpha
    • Complex: Mitogen-activated protein kinase 14 (MAPK p38alpha)
      • Protein or peptide: Mitogen-activated protein kinase 14
    • Complex: Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K MKK6)
      • Protein or peptide: Dual specificity mitogen-activated protein kinase kinase 6
  • Ligand: PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Complex between the MAP2K MKK6 and its substrate MAPK p38alpha

SupramoleculeName: Complex between the MAP2K MKK6 and its substrate MAPK p38alpha
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Molecular weightTheoretical: 80.2 KDa

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Supramolecule #2: Mitogen-activated protein kinase 14 (MAPK p38alpha)

SupramoleculeName: Mitogen-activated protein kinase 14 (MAPK p38alpha) / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K...

SupramoleculeName: Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K MKK6)
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Mitogen-activated protein kinase 14

MacromoleculeName: Mitogen-activated protein kinase 14 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: mitogen-activated protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.647727 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSSHHHHHH SSGLEVLFQG PMSQERPTFY RQELNKTIWE VPERYQNLSP VGSGAYGSVC AAFDTKTGLR VAVKKLSRPF QSIIHAKRT YRELRLLKHM KHENVIGLLD VFTPARSLEE FNDVYLVTHL MGADLNNIVK CQKLTDDHVQ FLIYQILRGL K YIHSADII ...String:
MGSSHHHHHH SSGLEVLFQG PMSQERPTFY RQELNKTIWE VPERYQNLSP VGSGAYGSVC AAFDTKTGLR VAVKKLSRPF QSIIHAKRT YRELRLLKHM KHENVIGLLD VFTPARSLEE FNDVYLVTHL MGADLNNIVK CQKLTDDHVQ FLIYQILRGL K YIHSADII HRDLKPSNLA VNEDCELKIL DFGLARHTDD EMVGYVATRW YRAPEIMLNW MHYNQTVDIW SVGCIMAELL TG RTLFPGT DHIDQLKLIL RLVGTPGAEL LKKISSESAR NYIQSLTQMP KMNFANVFIG ANPLAVDLLE KMLVLDSDKR ITA AQALAH AYFAQYHDPD DEPVADPYDQ SFESRDLLID EWKSLTYDEV ISFVPPPLDQ EEMES

UniProtKB: Mitogen-activated protein kinase 14

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Macromolecule #2: Dual specificity mitogen-activated protein kinase kinase 6

MacromoleculeName: Dual specificity mitogen-activated protein kinase kinase 6
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: mitogen-activated protein kinase kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.822844 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSQLLERRG VSELPPLYIP KEAFEQPQTS STPPRDLDSK ACISIGNQNF EVKADDLEPI MELGRGAYGV VEKMRHVPSG QIMAVKRIR ATVNSQEQKR LLMDLDISMR TVDCPFTVTF YGALFREGDV WICMELMDTS LDKFYKQVID KGQTIPEDIL G KIAVSIVK ...String:
MGSQLLERRG VSELPPLYIP KEAFEQPQTS STPPRDLDSK ACISIGNQNF EVKADDLEPI MELGRGAYGV VEKMRHVPSG QIMAVKRIR ATVNSQEQKR LLMDLDISMR TVDCPFTVTF YGALFREGDV WICMELMDTS LDKFYKQVID KGQTIPEDIL G KIAVSIVK ALEHLHSKLS VIHRDVKPSN VLINALGQVK MCDFGISGYL VDDVAKDIDA GCKPYMAPER INPELNQKGY SV KSDIWSL GITMIELAIL RFPYDSWGTP FQQLKQVVEE PSPQLPADKF SAEFVDFTSQ CLKKNSKERP TYPELMQHPF FTL HESKGT DVASFVKLIL GDLEVLFQGP WSHPQFEKGG GSGGGSGGSA WSHPQFEK

UniProtKB: Dual specificity mitogen-activated protein kinase kinase 6

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Macromolecule #3: PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER

MacromoleculeName: PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER / type: ligand / ID: 3 / Number of copies: 2 / Formula: AP2
Molecular weightTheoretical: 425.228 Da
Chemical component information

ChemComp-A12:
PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER

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Macromolecule #4: MAGNESIUM ION

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

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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

Concentration0.48 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
200.0 mMNaClsodium chloride
10.0 mMMgCl2magnesium chloride
50.0 mMHEPESHEPES
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 101.325 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV / Details: blot for 3.5 seconds.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
TemperatureMin: 70.0 K / Max: 70.0 K
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 3 / Number real images: 28633 / Average electron dose: 62.77 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 215000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.2) / Number images used: 35123
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.2)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

5etc

source_name: PDB, initial_model_type: experimental model

5eta

source_name: PDB, initial_model_type: experimental model

6yg1

source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8a8m:
Structure of the MAPK p38alpha in complex with its activating MAP2K MKK6

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