id: Q9UKB3 gene_symbol: DNAJC12 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 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. alternative_products: - name: a (JDP1a) id: Q9UKB3-1 - name: B (JDP1b) id: Q9UKB3-2 sequence_note: VSP_001295, VSP_001296 existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: 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. action: ACCEPT reason: Cytoplasm is the experimentally supported site of action of DNAJC12 (PMID:24122553 IDA). supported_by: - reference_id: file:human/DNAJC12/DNAJC12-uniprot.txt supporting_text: '[Isoform a]: Cytoplasm' - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated subcellular-location transfer of cytoplasmic localization, consistent with the experimentally established compartment. action: ACCEPT reason: Cytoplasm is the experimentally supported compartment of DNAJC12. supported_by: - reference_id: file:human/DNAJC12/DNAJC12-uniprot.txt supporting_text: '[Isoform a]: Cytoplasm' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: 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. action: KEEP_AS_NON_CORE reason: Bare protein binding is uninformative; this interaction reflects the hydroxylase-client binding that underlies DNAJC12's chaperone function, captured in the core functions. supported_by: - reference_id: file:human/DNAJC12/DNAJC12-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442 UniProtKB:P17752 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex affinity-purification interactome capturing a DNAJC12-TPH1 (P17752) interaction. The bare protein binding term reflects binding to a hydroxylase client. action: KEEP_AS_NON_CORE reason: Bare protein binding is uninformative; the TPH1 interaction reflects the hydroxylase-client binding underlying DNAJC12's chaperone function. supported_by: - reference_id: file:human/DNAJC12/DNAJC12-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:P17752 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24122553 qualifier: enables review: 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. action: MODIFY 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_replacement_terms: - id: GO:0030544 label: Hsp70 protein binding supported_by: - reference_id: PMID:24122553 supporting_text: The most frequently identified partner of DNAJC12 in unstressed cells was Hsc70, a cognate Hsp70 chaperone - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:24122553 qualifier: located_in review: summary: Direct immunofluorescence evidence that DNAJC12 is diffusely distributed in the cytoplasm. action: ACCEPT reason: Cytoplasm is the experimentally established compartment where DNAJC12 acts. supported_by: - reference_id: PMID:24122553 supporting_text: a recombinant DNAJC12 protein is diffusely distributed in the cytoplasm references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: PMID:24122553 title: The co-chaperone DNAJC12 binds to Hsc70 and is upregulated by endoplasmic reticulum stress. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached publication title matches PubMed; body confirms DNAJC12 binds Hsc70 (HSPA8) and is a cytoplasmic stress-upregulated co-chaperone. GOA anchors this PMID to GO:0005737 (cytoplasm, IDA) and GO:0005515, supporting DNAJC12's core J-domain co-chaperone function. findings: - statement: DNAJC12 binds the cognate Hsp70 chaperone Hsc70 (HSPA8) in unstressed cells and BiP under stress; it is cytoplasmic and up-regulated by ER stress, clarifying its role in regulating Hsp70 function. reference_section_type: ABSTRACT - id: PMID:28132689 title: Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached publication title matches PubMed; body confirms DNAJC12 is an HSP70 co-chaperone of the aromatic amino acid hydroxylases (PAH, TH, TPH) whose biallelic loss-of-function causes hyperphenylalaninemia with neurotransmitter deficiency, establishing the gene's in-vivo specific-client chaperone function. findings: - statement: DNAJC12 is an HSP70-family co-chaperone that interacts with phenylalanine hydroxylase (PAH), tyrosine hydroxylase and tryptophan hydroxylase; biallelic loss-of-function causes non-BH4-deficient hyperphenylalaninemia with dopamine/serotonin deficiency, dystonia and intellectual disability. reference_section_type: ABSTRACT - statement: PAH enzyme activity is reduced in the presence of DNAJC12 mutations; the J domain (HPD motif) stimulates HSP70 ATPase activity. reference_section_type: RESULTS - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: file:human/DNAJC12/DNAJC12-uniprot.txt title: UniProt entry Q9UKB3 (DJC12_HUMAN), DnaJ homolog subfamily C member 12 / JDP1 findings: - statement: Probable co-chaperone participating in proper folding of biopterin-dependent aromatic amino acid hydroxylases (PAH, TH, TPH1, TPH2); interacts with HSPA8/Hsc70; cytoplasmic; loss-of-function causes non-BH4-deficient hyperphenylalaninemia. reference_section_type: OTHER core_functions: - description: Cytosolic J-domain co-chaperone of the HSP70 family that binds the cognate Hsp70 chaperone Hsc70 (HSPA8) and stimulates HSP70 ATPase activity via its J-domain HPD motif. molecular_function: id: GO:0030544 label: Hsp70 protein binding locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:24122553 supporting_text: The most frequently identified partner of DNAJC12 in unstressed cells was Hsc70, a cognate Hsp70 chaperone - reference_id: PMID:28132689 supporting_text: DNAJC12 encodes a co-chaperone of the HSP70 family which interacts with PAH, tyrosine hydroxylase, and tryptophan hydroxylase - description: Dedicated co-chaperone for the biopterin-dependent aromatic amino acid hydroxylases (PAH, TH, TPH1, TPH2), binding these clients and assisting their proper folding and stability; loss of function reduces PAH activity and causes hyperphenylalaninemia. molecular_function: id: GO:0051087 label: protein-folding chaperone binding locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/DNAJC12/DNAJC12-uniprot.txt supporting_text: Probable co-chaperone that participates in the proper folding of biopterin-dependent aromatic amino acid hydroxylases, which include phenylalanine-4-hydroxylase (PAH), tyrosine 3-monooxygenase (TH) and peripheral and neuronal tryptophan hydroxylases (TPH1 and TPH2). - reference_id: PMID:28132689 supporting_text: PAH enzyme activity was reduced in the presence of DNAJC12 mutations proposed_new_terms: [] suggested_questions: - question: 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? - question: Why does DNAJC12 deficiency preferentially manifest as hyperphenylalaninemia with neurotransmitter deficiency, and what determines the variable neurological severity among patients? suggested_experiments: - description: 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. - description: 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.