Structural recognition and stabilization of
tyrosine hydroxylase by the J-domain protein DNAJC12.
Tai MDS, Ochoa L, Flydal MI, Velasco-Carneros L, Muntaner J, Santiago C,
Gamiz-Arco G, Moro F, Jung-Kc K, Gil-Cantero D, Marcilla M, Kallio JP, Muga A,
Valpuesta JM, Cuéllar J, Martinez A. Nat Commun. 2025 Mar
20;16(1):2755. doi: 10.1038/s41467-025-57733-6.
Genetic variants in the chaperone DNAJC12 are associated with diseases such as infantile parkinsonism with dystonia and severe neonatal onset encephalopathy. Previous research has shown that DNAJC2 is an essential molecular chaperone in the folding of enzymes involved in the synthesis of important neurotransmitters, such as dopamine. However, the molecular mechanism behind the effect of DNAJC12 mutations was unknown. Now, an international consortium, including teams from the Spanish National Research Council (CSIC) and the Universities of the Basque Country and Bergen (Norway), has characterised at functional and structural level the interaction between the DNAJC12 chaperone and the enzyme tyrosine hydroxylase (TH). TH catalyses the rate-limiting step in the synthesis of dopamine, explaining the severe physiological effects of DNAJC12 mutations. The work, published in Nature Communications, elucidates in molecular terms how the malfunction of this chaperone leads to disorders with symptoms similar to parkinsonism and neurometabolic diseases associated with decreased dopamine levels.
Proper regulation of protein levels and their functioning is key to cell survival. For this reason, organisms have developed systems to prevent misalignments that could lead to a multitude of diseases. One of the major control systems involves molecular chaperones, with a common function: to ensure that cellular proteins have the right conformation to function. In the case of DNAJC12, there are several known mutations that result in its deficiency, causing parkinsonism – a syndrome that includes typical motor symptoms of Parkinson’s disease and neurometabolic diseases associated with low dopamine levels. These mutations affect DNAJC12’s interaction with TH, resulting in its instability and dysfunction, in a similar manner as observed in the case of mutations in TH, that lead to a disease called TH deficiency (THD), associated with infantile parkinsonism with dystonia or severe neonatal onset encephalopathy. In other words, a defective interaction of DNAJC12 with TH due to mutations in the chaperone is a key point for the appearance of parkinsonism and similar syndromes, highlighting the importance of understanding how mutations in DNAJC12 affect the function of both proteins.
Using molecular biology and biophysical techniques combined with advanced structural tools such as cryoelectron microscopy, the team has revealed the nature of the interaction between TH and DNAJC12, not only at the physical level, but also at the functional level. DNAJC12 chaperone binds to TH with high affinity, stabilizing the functional conformation of the enzyme and avoiding the formation of aggregates that could compromise neuronal activity. In addition, the study used recombinant proteins containing the same mutations identified in patients with these syndromes, allowing the team to understand how these variants interfere with the interaction between TH and DNAJC12, as well as the necessary level of neurotransmitter for proper neurological function. This study helps to explain in molecular terms why the malfunctioning of mutants of this chaperone leads to some of the aforementioned diseases.
