Structural recognition and stabilization of tyrosine hydroxylase by the J-domain protein DNAJC12.
Level 5 - mechanism / opinion, no new human data
Bench research (in vitro structural biology and biochemical characterization) with no human clinical data.
PubMed 40113792 · doi:10.1038/s41467-025-57733-6
What was done
The authors investigated the molecular mechanism of interaction between the molecular co-chaperone DNAJC12 and tyrosine hydroxylase (TH, including the deficiency-associated variant TH-p.R202H). They utilized cryo-electron microscopy and crosslinking-mass spectrometry to determine the architectural basis of the complex, alongside biochemical assays measuring protein aggregation, enzymatic activity, feedback inhibition by dopamine, and Hsc70 ATPase activation.
What was found
The abstract reports no numerical values. DNAJC12 binding stabilized both wild-type TH and TH-p.R202H, slowing time-dependent aggregation in an Hsp70-independent manner without disrupting baseline TH activity or dopamine feedback inhibition. When bound to TH, DNAJC12 synergistically stimulated Hsc70 ATPase activity. Structural analyses revealed a stoichiometry of two DNAJC12 monomers bound to regulatory domain dimers per TH tetramer, maintaining active site accessibility and identifying the C-terminal region of DNAJC12 as critical for binding.
Why it matters
This study provides the structural mechanism for how DNAJC12 selectively stabilizes tyrosine hydroxylase, elucidating how pathogenic mutations disrupting this chaperone-client interface cause dopamine deficiency and parkinsonism.
Limits
The findings are limited to cell-free in vitro structural and biochemical assays. The abstract provides no quantitative parameters (e.g., binding affinities, aggregation kinetics, or resolution), and physiological validation in cellular or in vivo models was not reported.
Cited by
- contradicts Tyrosinase is the rate-limiting enzyme for dopamine production in the body.