id: Q9NNZ3 gene_symbol: DNAJC4 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: DNAJC4 (DnaJ homolog subfamily C member 4; also called DnaJ-like protein HSPF2 and MEN1 candidate protein 18, MCG18) is a poorly characterized member of the DnaJ/HSP40 (type III, "C") co-chaperone family. It comprises an N-terminal J domain (the signature HPD-motif-containing module that engages and stimulates HSP70 chaperones), a disordered central region, and a predicted single-pass transmembrane helix near the C-terminus, consistent with annotation as a membrane protein. By family assignment it is expected to act as an HSP70 co-chaperone, but no direct biochemical characterization of its chaperone activity or client repertoire has been reported. It is expressed broadly with enhancement in testis. existing_annotations: - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Electronic annotation of membrane localization, consistent with the UniProt single-pass transmembrane prediction. action: ACCEPT reason: A predicted helical transmembrane segment (residues 156-175) and UniProt annotation as a single-pass membrane protein support membrane localization; this is the best-supported compartment for DNAJC4. supported_by: - reference_id: file:human/DNAJC4/DNAJC4-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Membrane' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17500595 qualifier: enables review: summary: IntAct capture of a DNAJC4-HTT (huntingtin) interaction from a huntingtin-interactor screen. The bare protein binding term is uninformative and the partner does not define a chaperone function for DNAJC4. action: KEEP_AS_NON_CORE reason: Records a real but uninformative high-throughput interaction with huntingtin; per curation guidelines, bare protein binding is not elevated to core and there is no specific informative MF that this single interaction establishes for DNAJC4. supported_by: - reference_id: file:human/DNAJC4/DNAJC4-uniprot.txt supporting_text: 'Q9NNZ3; P42858: HTT; NbExp=12' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: Neurodegeneration-focused interactome screen capturing a DNAJC4-WFS1 (wolframin) interaction. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real high-throughput interaction (with WFS1) but is uninformative as a molecular function; not elevated to core. supported_by: - reference_id: file:human/DNAJC4/DNAJC4-uniprot.txt supporting_text: 'Q9NNZ3; O76024: WFS1; NbExp=3' - term: id: GO:0006986 label: response to unfolded protein evidence_type: TAS original_reference_id: PMID:9473517 qualifier: involved_in review: summary: Process annotation derived from the original cloning paper, reflecting the family-level expectation that a DnaJ protein participates in the unfolded-protein/stress response rather than a demonstrated role for DNAJC4 specifically. action: KEEP_AS_NON_CORE reason: Plausible family-level inference from the DnaJ/HSP40 assignment but not experimentally demonstrated for DNAJC4; retained as a non-core process. supported_by: - reference_id: file:human/DNAJC4/DNAJC4-uniprot.txt supporting_text: DnaJ-like protein HSPF2 - term: id: GO:0016020 label: membrane evidence_type: TAS original_reference_id: PMID:9473517 qualifier: located_in review: summary: Curated (TAS) membrane localization from the cloning paper, redundant with and consistent with the IEA membrane annotation and the predicted transmembrane helix. action: ACCEPT reason: Agrees with the predicted single-pass transmembrane segment and UniProt membrane assignment. supported_by: - reference_id: file:human/DNAJC4/DNAJC4-uniprot.txt supporting_text: Single-pass membrane protein - term: id: GO:0006457 label: protein folding evidence_type: NAS original_reference_id: PMID:9473517 qualifier: involved_in review: summary: Non-traceable author statement that DNAJC4 participates in protein folding, a family-level inference for a DnaJ/HSP40 co-chaperone. DnaJ proteins are co-chaperones that assist HSP70 rather than autonomous foldases. action: KEEP_AS_NON_CORE reason: Protein folding is a downstream process outcome of the HSP70 system that J-domain co-chaperones assist; it is a plausible but non-core, inference-level annotation for this uncharacterized protein. supported_by: - reference_id: file:human/DNAJC4/DNAJC4-uniprot.txt supporting_text: DnaJ-like protein HSPF2 - term: id: GO:0016020 label: membrane evidence_type: NAS original_reference_id: PMID:9473517 qualifier: located_in review: summary: Non-traceable author statement of membrane localization, redundant with the TAS and IEA membrane annotations. action: ACCEPT reason: Consistent with the predicted transmembrane helix and UniProt membrane assignment. supported_by: - reference_id: file:human/DNAJC4/DNAJC4-uniprot.txt supporting_text: Single-pass membrane protein references: - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:17500595 title: Huntingtin interacting proteins are genetic modifiers of neurodegeneration. findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - id: PMID:9473517 title: Characterisation of a new human and murine member of the DnaJ family of proteins. reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: "Primary reference establishing DNAJC4/HSPF2 as a new DnaJ/HSP40 family member; the family assignment underlies the inferred HSP70 co-chaperone molecular function and membrane localization. Not cached in publications/, so the identifier and supporting content could not be checked against a PubMed/ cached anchor; title is consistent with the claim but left UNVERIFIED." findings: - statement: DNAJC4/HSPF2 was identified as a new member of the DnaJ/HSP40 family; assignment to this family is the basis for its inferred protein-folding/unfolded-protein-response and membrane annotations. reference_section_type: RESULTS core_functions: - description: Predicted HSP70 (DnaJ/HSP40) co-chaperone, defined by an N-terminal J domain that in characterized family members engages and stimulates HSP70 chaperones. No direct experimental characterization of DNAJC4's activity or clients exists, so this is a family-level molecular assignment rather than a verified function. molecular_function: id: GO:0051082 label: unfolded protein binding locations: - id: GO:0016020 label: membrane supported_by: - reference_id: file:human/DNAJC4/DNAJC4-uniprot.txt supporting_text: DnaJ-like protein HSPF2 proposed_new_terms: [] suggested_questions: - question: Does DNAJC4 function as a bona fide HSP70 co-chaperone (i.e. does its J domain stimulate HSP70 ATPase activity), and which HSP70 paralog does it partner with? - question: What is the topology and subcellular destination of the predicted single-pass transmembrane DNAJC4, and does it act on a specific membrane compartment? suggested_experiments: - description: In vitro single-turnover and steady-state ATPase assays with purified DNAJC4 J domain plus HSPA8/HSPA1A to test whether DNAJC4 stimulates HSP70 ATPase activity, with a J-domain HPD-motif mutant as negative control. - description: Tagged-DNAJC4 affinity purification-mass spectrometry from a relevant cell type to define its interactome and any specific client or HSP70 partner beyond the existing high-throughput hits.