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

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 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 embra

SUBMITTER: Tai MDS 

PROVIDER: S-EPMC11926245 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature