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- EMDB-18058: TH-DNAJC12 (108-198) -

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Basic information

Entry
Database: EMDB / ID: EMD-18058
TitleTH-DNAJC12 (108-198)
Map dataTH-DNAJC12D107 3DR
Sample
  • Complex: TH-DNAJC12 (108-198) Complex
    • Protein or peptide: Tyrosine Hydroxylate
    • Protein or peptide: DNAJC12 (108-198)
KeywordsDNAJC12 Hsp40 Hsp70 Tyrosine hydroxylate deficiency / CHAPERONE
Function / homology
Function and homology information


tyrosine 3-monooxygenase / tyrosine 3-monooxygenase activity / dopamine biosynthetic process from tyrosine / embryonic camera-type eye morphogenesis / epinephrine biosynthetic process / Catecholamine biosynthesis / norepinephrine biosynthetic process / hyaloid vascular plexus regression / eye photoreceptor cell development / melanosome membrane ...tyrosine 3-monooxygenase / tyrosine 3-monooxygenase activity / dopamine biosynthetic process from tyrosine / embryonic camera-type eye morphogenesis / epinephrine biosynthetic process / Catecholamine biosynthesis / norepinephrine biosynthetic process / hyaloid vascular plexus regression / eye photoreceptor cell development / melanosome membrane / synaptic transmission, dopaminergic / mating behavior / eating behavior / dopamine biosynthetic process / pigmentation / regulation of heart contraction / smooth endoplasmic reticulum / anatomical structure morphogenesis / heart morphogenesis / visual perception / animal organ morphogenesis / learning / locomotory behavior / cytoplasmic side of plasma membrane / memory / synaptic vesicle / heart development / cytoplasmic vesicle / response to ethanol / perikaryon / response to hypoxia / neuron projection / iron ion binding / axon / perinuclear region of cytoplasm / enzyme binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
J domain-containing protein 1-like / Tyrosine 3-monooxygenase / Tyrosine hydroxylase, conserved site / Tyrosine 3-monooxygenase, catalytic domain / : / Tyrosine hydroxylase N terminal / Tyrosine 3-monooxygenase-like, ACT domain / Tyrosine 3-monooxygenase-like / Aromatic amino acid hydroxylase, iron/copper binding site / Biopterin-dependent aromatic amino acid hydroxylases signature. ...J domain-containing protein 1-like / Tyrosine 3-monooxygenase / Tyrosine hydroxylase, conserved site / Tyrosine 3-monooxygenase, catalytic domain / : / Tyrosine hydroxylase N terminal / Tyrosine 3-monooxygenase-like, ACT domain / Tyrosine 3-monooxygenase-like / Aromatic amino acid hydroxylase, iron/copper binding site / Biopterin-dependent aromatic amino acid hydroxylases signature. / Aromatic amino acid hydroxylase / Aromatic amino acid hydroxylase, C-terminal / Aromatic amino acid monoxygenase, C-terminal domain superfamily / Aromatic amino acid hydroxylase superfamily / Biopterin-dependent aromatic amino acid hydroxylase / Biopterin-dependent aromatic amino acid hydroxylase family profile. / DnaJ domain / ACT-like domain / DnaJ molecular chaperone homology domain / dnaJ domain profile. / Chaperone J-domain superfamily / DnaJ domain
Similarity search - Domain/homology
Tyrosine 3-monooxygenase / DnaJ homolog subfamily C member 12
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.05 Å
AuthorsOchoa L / Tai MDS / Muntaner J / Santiago C / Valpuesta JM / Martinez A / Cuellar J
Funding support Spain, Norway, 2 items
OrganizationGrant numberCountry
Spanish Ministry of Science, Innovation, and UniversitiesPID2019-105872GB-I00/AEI/10.13039/ 501100011033 Spain
Research Council of NorwayFRIMEDBIO 261826 Norway
CitationJournal: Nat Commun / Year: 2025
Title: Structural recognition and stabilization of tyrosine hydroxylase by the J-domain protein DNAJC12.
Authors: Mary Dayne S Tai / Lissette Ochoa / Marte I Flydal / Lorea Velasco-Carneros / Jimena Muntaner / César Santiago / Gloria Gamiz-Arco / Fernando Moro / Kunwar Jung-Kc / David Gil-Cantero / ...Authors: Mary Dayne S Tai / Lissette Ochoa / Marte I Flydal / Lorea Velasco-Carneros / Jimena Muntaner / César Santiago / Gloria Gamiz-Arco / Fernando Moro / Kunwar Jung-Kc / David Gil-Cantero / Miguel Marcilla / Juha P Kallio / Arturo Muga / José María Valpuesta / Jorge Cuéllar / Aurora Martinez /
Abstract: Pathogenic variants of the J-domain protein DNAJC12 cause parkinsonism, which is associated with a defective interaction of DNAJC12 with tyrosine hydroxylase (TH), the rate-limiting enzyme in ...Pathogenic variants of the J-domain protein DNAJC12 cause parkinsonism, which is associated with a defective interaction of DNAJC12 with tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. In this work, we characterize the formation of the TH:DNAJC12 complex, showing that DNAJC12 binding stabilizes both TH and the variant TH-p.R202H, associated with TH deficiency. This binding delays their time-dependent aggregation in an Hsp70-independent manner, while preserving TH activity and feedback regulatory inhibition by dopamine. DNAJC12 alone barely activates Hsc70 but synergistically stimulates Hsc70 ATPase activity when complexed with TH. Cryo-electron microscopy supported by crosslinking-mass spectroscopy reveals two DNAJC12 monomers bound per TH tetramer, each embracing one of the two regulatory domain dimers, leaving the active sites available for substrate, cofactor and inhibitory dopamine interaction. Our results also reveal the key role of the C-terminal region of DNAJC12 in TH binding, explaining the pathogenic mechanism of the DNAJC12 disease variant p.W175Ter.
History
DepositionJul 28, 2023-
Header (metadata) releaseFeb 5, 2025-
Map releaseFeb 5, 2025-
UpdateSep 3, 2025-
Current statusSep 3, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18058.png

Downloads & links

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Map

FileDownload / File: emd_18058.map.gz / Format: CCP4 / Size: 1.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTH-DNAJC12D107 3DR
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
2.46 Å/pix.
x 76 pix.
= 186.998 Å		2.46 Å/pix.
x 76 pix.
= 186.998 Å		2.46 Å/pix.
x 76 pix.
= 186.998 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 2.4605 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0221
Minimum - Maximum-0.09117123 - 0.19730619
Average (Standard dev.)0.000857063 (±0.0123573)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions767676
Spacing767676
CellA=B=C: 186.998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: TH-DNAJC12D107 3D halfmap 1

Fileemd_18058_half_map_1.map
AnnotationTH-DNAJC12D107 3D halfmap 1
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: TH-DNAJC12D107 3D halfmap 2

Fileemd_18058_half_map_2.map
AnnotationTH-DNAJC12D107 3D halfmap 2
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : TH-DNAJC12 (108-198) Complex

EntireName: TH-DNAJC12 (108-198) Complex
Components
  • Complex: TH-DNAJC12 (108-198) Complex
    • Protein or peptide: Tyrosine Hydroxylate
    • Protein or peptide: DNAJC12 (108-198)

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Supramolecule #1: TH-DNAJC12 (108-198) Complex

SupramoleculeName: TH-DNAJC12 (108-198) Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 265 KDa

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Macromolecule #1: Tyrosine Hydroxylate

MacromoleculeName: Tyrosine Hydroxylate / type: protein_or_peptide / ID: 1 / Enantiomer: DEXTRO / EC number: tyrosine 3-monooxygenase
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: GAMGPTPDAT TPQAKGFRRA VSELDAKQAE AIMSPRFIGR RQSLIEDARK EREAAVAAAA AAVPSEPGDP LEAVAFEEKE GKAMLNLLFS PRATKPSALS RAVKVFETFE AKIHHLETRP AQRPRAGGPH LEYFVRLEVR RGDLAALLSG VRQVSEDVRS PAGPKVPWFP ...String:
GAMGPTPDAT TPQAKGFRRA VSELDAKQAE AIMSPRFIGR RQSLIEDARK EREAAVAAAA AAVPSEPGDP LEAVAFEEKE GKAMLNLLFS PRATKPSALS RAVKVFETFE AKIHHLETRP AQRPRAGGPH LEYFVRLEVR RGDLAALLSG VRQVSEDVRS PAGPKVPWFP RKVSELDKCH HLVTKFDPDL DLDHPGFSDQ VYRQRRKLIA EIAFQYRHGD PIPRVEYTAE EIATWKEVYT TLKGLYATHA CGEHLEAFAL LERFSGYRED NIPQLEDVSR FLKERTGFQL RPVAGLLSAR DFLASLAFRV FQCTQYIRHA SSPMHSPEPD CCHELLGHVP MLADRTFAQF SQDIGLASLG ASDEEIEKLS TLYWFTVEFG LCKQNGEVKA YGAGLLSSYG ELLHCLSEEP EIRAFDPEAA AVQPYQDQTY QSVYFVSESF SDAKDKLRSY ASRIQRPFSV KFDPYTLAID VLDSPQAVRR SLEGVQDELD TLAHALSAIG

UniProtKB: Tyrosine 3-monooxygenase

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Macromolecule #2: DNAJC12 (108-198)

MacromoleculeName: DNAJC12 (108-198) / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GKKDLMLEES DKTHTTKMEN EECNEQRERK KEELASTAEK TEQKEPKPLE KSVSPQNSDS SGFADVNGWH LRFRWSKDAP SELLRKFRNY EI

UniProtKB: DnaJ homolog subfamily C member 12

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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

Concentration1.85 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
30.0 mMC8H18N2O4SHepes
200.0 mMNaClSodium chloride
2.0 %C3H8O3Glycerol
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 295.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Digitization - Dimensions - Width: 3456 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 12996 / Average exposure time: 2.1 sec. / Average electron dose: 41.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 105000
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

Particle selectionNumber selected: 1283996
CTF correctionSoftware - Name: Gctf / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7a2g


Details: Cryosparc, RANSAC initial model and filtered atomic structures
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.05 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 128537
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software: (Name: RELION (ver. 3.0), cryoSPARC (ver. 3.0)) / Details: Relion and Cryosparc
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0) / Details: Relion
Final 3D classificationNumber classes: 3 / Software - Name: RELION (ver. 3.0)
FSC plot (resolution estimation)

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