DNAJC12 (also called JDP1) is a small cytosolic "J domain-only" co-chaperone of the DnaJ/Hsp40 (DNAJC) family, consisting of an N-terminal J domain (with the conserved HPD motif) and a C-terminal intrinsically disordered region. As a co-chaperone of the HSP70 family, it binds the cognate Hsp70 chaperone Hsc70 (HSPA8) and, through its J domain, stimulates HSP70 ATPase activity. DNAJC12 is a dedicated chaperone for the biopterin (BH4)-dependent aromatic amino acid hydroxylases, interacting with phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH) and tryptophan hydroxylases (TPH1, TPH2) and assisting their proper folding and stability. It is diffusely cytoplasmic and is up-regulated by ER stress. Biallelic loss-of-function variants cause autosomal-recessive non-BH4-deficient hyperphenylalaninemia accompanied by dopamine and serotonin deficiency, dystonia/parkinsonism and intellectual disability, a condition treatable with BH4 and neurotransmitter precursors.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred cytoplasmic localization, consistent with the experimentally established cytoplasmic localization where DNAJC12 acts as an HSP70 co-chaperone for aromatic amino acid hydroxylases. Reason: Cytoplasm is the experimentally supported site of action of DNAJC12 (PMID:24122553 IDA). Supporting Evidence: file:human/DNAJC12/DNAJC12-uniprot.txt [Isoform a]: Cytoplasm |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Automated subcellular-location transfer of cytoplasmic localization, consistent with the experimentally established compartment. Reason: Cytoplasm is the experimentally supported compartment of DNAJC12. Supporting Evidence: file:human/DNAJC12/DNAJC12-uniprot.txt [Isoform a]: Cytoplasm |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: Interaction (IntAct WITH tryptophan hydroxylase 1, TPH1, P17752). The bare protein binding term records a real client interaction but is uninformative; it reflects DNAJC12's binding to an aromatic amino acid hydroxylase client. Reason: Bare protein binding is uninformative; this interaction reflects the hydroxylase-client binding that underlies DNAJC12's chaperone function, captured in the core functions. Supporting Evidence: file:human/DNAJC12/DNAJC12-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442 UniProtKB:P17752 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex affinity-purification interactome capturing a DNAJC12-TPH1 (P17752) interaction. The bare protein binding term reflects binding to a hydroxylase client. Reason: Bare protein binding is uninformative; the TPH1 interaction reflects the hydroxylase-client binding underlying DNAJC12's chaperone function. Supporting Evidence: file:human/DNAJC12/DNAJC12-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:P17752 |
| GO:0005515 protein binding | IPI PMID:24122553 The co-chaperone DNAJC12 binds to Hsc70 and is upregulated b... | MODIFY | Summary: Immunoaffinity-MS and co-IP showing DNAJC12 interacts with the cognate Hsp70 chaperone Hsc70 (HSPA8, P11142). The bare protein binding term is uninformative; the interaction is specifically with an HSP70-family chaperone. Reason: Bare protein binding is uninformative. The documented partner is the Hsp70 chaperone Hsc70/HSPA8, so the informative molecular function is Hsp70 protein binding (GO:0030544). Proposed replacements: Hsp70 protein binding Supporting Evidence: PMID:24122553 The most frequently identified partner of DNAJC12 in unstressed cells was Hsc70, a cognate Hsp70 chaperone |
| GO:0005737 cytoplasm | IDA PMID:24122553 The co-chaperone DNAJC12 binds to Hsc70 and is upregulated b... | ACCEPT | Summary: Direct immunofluorescence evidence that DNAJC12 is diffusely distributed in the cytoplasm. Reason: Cytoplasm is the experimentally established compartment where DNAJC12 acts. Supporting Evidence: PMID:24122553 a recombinant DNAJC12 protein is diffusely distributed in the cytoplasm |
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Download this section (compressed HTML)Q: Does DNAJC12 recognize a shared structural feature of the aromatic amino acid hydroxylase fold, and how does it coordinate Hsc70 with BH4 cofactor loading during hydroxylase maturation?
Q: Why does DNAJC12 deficiency preferentially manifest as hyperphenylalaninemia with neurotransmitter deficiency, and what determines the variable neurological severity among patients?
Experiment: Reconstitute PAH (and TH/TPH) folding/stability in vitro with DNAJC12, Hsc70 and ATP, comparing wild-type versus HPD-motif and disease (e.g. R72P) mutants to dissect the J-domain-dependent contribution to client maturation.
Experiment: Quantify aromatic amino acid hydroxylase levels and activities, and dopamine/serotonin output, in DNAJC12-knockout neuronal models with and without BH4 supplementation to define the chaperone's role across the hydroxylase family.
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