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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


nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / mitogen-activated protein kinase kinase / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / negative regulation of cold-induced thermogenesis / positive regulation of myoblast fusion / cartilage condensation / stress-activated protein kinase signaling cascade / 3'-UTR-mediated mRNA stabilization ...nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / mitogen-activated protein kinase kinase / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / negative regulation of cold-induced thermogenesis / positive regulation of myoblast fusion / cartilage condensation / stress-activated protein kinase signaling cascade / 3'-UTR-mediated mRNA stabilization / CD163 mediating an anti-inflammatory response / positive regulation of cyclase activity / response to dietary excess / positive regulation of myotube differentiation / positive regulation of muscle cell differentiation / cellular response to UV-B / KSRP (KHSRP) binds and destabilizes mRNA / mitogen-activated protein kinase p38 binding / Myogenesis / Platelet sensitization by LDL / NFAT protein binding / cellular response to lipoteichoic acid / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / p38MAPK cascade / ERK/MAPK targets / PI5P Regulates TP53 Acetylation / MAP kinase kinase activity / Regulation of MITF-M-dependent genes involved in pigmentation / MAP kinase activity / cellular response to vascular endothelial growth factor stimulus / Uptake and function of anthrax toxins / mitogen-activated protein kinase / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / RHO GTPases Activate NADPH Oxidases / positive regulation of myoblast differentiation / negative regulation of hippo signaling / osteoclast differentiation / positive regulation of interleukin-12 production / signal transduction in response to DNA damage / p38MAPK events / positive regulation of erythrocyte differentiation / regulation of signal transduction by p53 class mediator / tumor necrosis factor-mediated signaling pathway / response to insulin / cellular response to ionizing radiation / cellular response to virus / activated TAK1 mediates p38 MAPK activation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / platelet activation / bone development / NOD1/2 Signaling Pathway / PKR-mediated signaling / VEGFA-VEGFR2 Pathway / cellular senescence / chemotaxis / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Interleukin-1 signaling / MAPK cascade / ADP signalling through P2Y purinoceptor 1 / cellular response to lipopolysaccharide / spindle pole / protein tyrosine kinase activity / secretory granule lumen / protein phosphatase binding / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / cytoskeleton / regulation of cell cycle / cell surface receptor signaling pathway / nuclear speck / intracellular signal transduction / apoptotic process / protein serine kinase activity / protein serine/threonine kinase activity / positive regulation of gene expression / regulation of transcription by RNA polymerase II / Neutrophil degranulation / protein kinase binding / glutamatergic synapse / enzyme binding / signal transduction / DNA-templated transcription / mitochondrion / nucleoplasm / extracellular region / ATP binding / identical protein binding / nucleus / cytosol / cytoplasm
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-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing 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
Contrast
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)

Slices (1/2)

Slices (2/3)

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
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_15233_half_map_1.map
Annotationhalf map A
Projections & Slices
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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
Projections & Slices
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Histogram (log scale)

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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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