Structural recognition and stabilization of tyrosine hydroxylase by the J-domain protein DNAJC12

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Abstract Pathogenic variants of the J-domain protein and Hsp70 cochaperone DNAJC12 cause parkinsonism, which is associated with a defective interaction of DNAJC12 with tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine (DA) biosynthesis. Here, we report the characterization of TH:DNAJC12 complex formation, showing that DNAJC12 binding stabilizes TH and delays its time-dependent aggregation in an Hsp70-independent manner, while maintaining TH activity and regulatory inhibition by DA. Interestingly, DNAJC12 alone barely activated Hsc70, the constitutively-expressed Hsp70 isoform, but in complex with TH, DNAJC12 efficiently stimulated Hsc70 ATPase activity. Cryoelectron microscopy revealed two DNAJC12 monomers bound per TH tetramer, each embracing one of the two regulatory domain dimers, leaving all active sites available for substrate and DA interaction. Our results confirm the key role of the C-terminal eight residues of DNAJC12 in TH binding, explaining the pathogenic mechanism of the disease variant DNAJC12(Trp175Ter).

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