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

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 () and Aurora Martinez ()
Additional contact information
Mary Dayne S. Tai: University of Bergen
Lissette Ochoa: Centro Nacional de Biotecnología (CNB-CSIC)
Marte I. Flydal: University of Bergen
Lorea Velasco-Carneros: Barrio Sarriena
Jimena Muntaner: Centro Nacional de Biotecnología (CNB-CSIC)
César Santiago: Centro Nacional de Biotecnología (CNB-CSIC)
Gloria Gamiz-Arco: University of Bergen
Fernando Moro: Barrio Sarriena
Kunwar Jung-KC: University of Bergen
David Gil-Cantero: Centro Nacional de Biotecnología (CNB-CSIC)
Miguel Marcilla: Centro Nacional de Biotecnología (CNB-CSIC)
Juha P. Kallio: University of Bergen
Arturo Muga: Barrio Sarriena
José María Valpuesta: Centro Nacional de Biotecnología (CNB-CSIC)
Jorge Cuéllar: Centro Nacional de Biotecnología (CNB-CSIC)
Aurora Martinez: University of Bergen

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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 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.

Date: 2025
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DOI: 10.1038/s41467-025-57733-6

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