id: Q99615 gene_symbol: DNAJC7 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: DNAJC7 (also called Tpr2 or TTC2) is a cytoplasmic co-chaperone of the DnaJ/Hsp40 (DNAJC) family that uniquely combines two tetratricopeptide-repeat (TPR) clusters with a C-terminal J domain. The TPR domains bind the molecular chaperones HSP70 and HSP90 simultaneously, while the J domain stimulates the ATPase activity and polypeptide binding of HSP70, allowing DNAJC7 to couple and regulate the HSP70 and HSP90 chaperone machines. It acts as a "recycling" co-chaperone that mediates retrograde transfer of folding substrates from HSP90 back onto HSP70, optimizing the maturation of clients such as the glucocorticoid and progesterone steroid receptors and protein kinases (e.g. CHK1). It is predominantly cytoplasmic but also localizes to the nucleus and associates with the cytoskeleton/microtubules; it interacts with the 9-1-1 checkpoint clamp (RAD9A-HUS1-RAD1) and recruits the nuclear receptor NR1I3/CAR to the cytoplasm. Loss-of-function variants in DNAJC7 are a recognized cause of/risk factor for amyotrophic lateral sclerosis (ALS) with TDP-43 pathology. alternative_products: - name: '1' id: Q99615-1 - name: '2' id: Q99615-2 sequence_note: VSP_044279 existing_annotations: - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated subcellular-location transfer placing DNAJC7 in the nucleus. Nuclear localization is genuine (experimentally observed and enhanced for the J-domain H409A mutant) but is secondary to the cytoplasmic site of action. action: KEEP_AS_NON_CORE reason: Nuclear localization is corroborated by experimental evidence (PMID:11573955) but is not where DNAJC7 performs its core HSP70/HSP90 co-chaperone function. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:11573955}.' - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated transfer of cytoplasmic localization, consistent with the experimentally established cytoplasmic site where DNAJC7 acts as an HSP70/HSP90 co-chaperone. action: ACCEPT reason: Cytoplasm is the primary, experimentally supported (PMID:12853476 IDA) compartment of DNAJC7 action. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005856 label: cytoskeleton evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated annotation of cytoskeletal localization, reflecting the by-similarity observation that DNAJC7 colocalizes with NR1I3 on microtubules. action: KEEP_AS_NON_CORE reason: Cytoskeletal/microtubule association is a specialized context (NR1I3/CAR sequestration), peripheral to the core co-chaperone function. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: Cytoplasm, cytoskeleton {ECO:0000250|UniProtKB:Q9QYI3}. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17043677 qualifier: enables review: summary: High-throughput interaction (IntAct WITH DISC1, Q9NRI5). The bare protein binding term records a real interaction but is uninformative about function. action: KEEP_AS_NON_CORE reason: Bare protein binding is uninformative per curation guidelines; retained as a recorded interaction, not elevated to core. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:17043677 UniProtKB:Q9NRI5 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22190034 qualifier: enables review: summary: High-throughput interaction (IntAct WITH HIV-1 vif, P12504, xeno). Bare protein binding term; biologically peripheral viral-host interaction. action: KEEP_AS_NON_CORE reason: Uninformative bare protein binding from a virus-host screen; not part of the core chaperone function. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:22190034 UniProtKB:P12504 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25036637 qualifier: enables review: summary: Quantitative chaperone interaction network (Taipale et al.) capturing DNAJC7 interactions with co-chaperones/clients including BAG2, BAG4 and HSPA1L. The bare term is uninformative, though the partners reflect the chaperone module. action: KEEP_AS_NON_CORE reason: Bare protein binding is uninformative; the informative chaperone-binding function is captured by the dedicated heat shock protein binding annotation. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25036637 UniProtKB:P34931 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26496610 qualifier: enables review: summary: High-throughput interaction (IntAct WITH BAG2, O95816). Bare protein binding term recording a co-chaperone interaction. action: KEEP_AS_NON_CORE reason: Bare protein binding is uninformative; retained as a recorded interaction. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:26496610 UniProtKB:O95816 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31413325 qualifier: enables review: summary: High-throughput interaction (IntAct WITH DISC1, Q9NRI5). Bare protein binding term. action: KEEP_AS_NON_CORE reason: Bare protein binding is uninformative; retained as a recorded interaction. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:31413325 UniProtKB:Q9NRI5 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex affinity-purification interactome (Huttlin et al.) capturing a DNAJC7-BAG2 (O95816) interaction. Bare protein binding term. action: KEEP_AS_NON_CORE reason: Bare protein binding is uninformative; retained as a recorded interaction. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:O95816 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 qualifier: enables review: summary: High-throughput interaction (IntAct WITH BAG4 O95429 and BAG2 O95816). Bare protein binding term recording co-chaperone interactions. action: KEEP_AS_NON_CORE reason: Bare protein binding is uninformative; retained as a recorded interaction. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:35271311 UniProtKB:O95429 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Multimodal cell-maps interactome capturing DNAJC7 interactions including BAG2 (O95816), HSPA1L (P34931) and MLF2 (Q15773). Bare protein binding term. action: KEEP_AS_NON_CORE reason: Bare protein binding is uninformative; retained as a recorded interaction. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054 UniProtKB:O95816 - term: id: GO:1900034 label: regulation of cellular response to heat evidence_type: TAS original_reference_id: Reactome:R-HSA-3371453 qualifier: involved_in review: summary: Reactome pathway annotation placing DNAJC7 in regulation of the HSF1-mediated heat shock response. As an HSP40 co-chaperone it participates in the proteostasis/HSR circuitry, a plausible but non-core downstream process. action: KEEP_AS_NON_CORE reason: Participation in the heat-shock response is a process-level consequence of the co-chaperone role rather than DNAJC7's direct molecular function. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:1900034 regulation of cellular response to heat biological_process ECO:0000304 TAS Reactome:R-HSA-3371453 - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: HPA immunofluorescence showing nucleoplasmic localization, consistent with the documented nuclear pool of DNAJC7. action: KEEP_AS_NON_CORE reason: Nucleoplasmic localization is genuine but secondary to the cytoplasmic site of the core co-chaperone function. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:11573955}.' - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: HPA immunofluorescence showing cytosolic localization, the primary compartment where DNAJC7 acts. action: ACCEPT reason: Cytosol is the principal, experimentally supported site of DNAJC7's co-chaperone activity. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005634 label: nucleus evidence_type: EXP original_reference_id: PMID:11573955 qualifier: located_in review: summary: Experimental evidence (interaction with the RAD9A checkpoint protein) for nuclear localization of DNAJC7. Genuine but secondary compartment. action: KEEP_AS_NON_CORE reason: Nuclear localization is experimentally supported but peripheral to the core cytoplasmic co-chaperone function. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:11573955}.' - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:11573955 qualifier: located_in review: summary: Experimental evidence for cytoplasmic localization of DNAJC7, its primary site of action. action: ACCEPT reason: Cytoplasm is the experimentally supported principal compartment of DNAJC7. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0001671 label: ATPase activator activity evidence_type: TAS original_reference_id: Reactome:R-HSA-5251955 qualifier: enables review: summary: DNAJC7's J domain stimulates ATP hydrolysis by HSP70, the defining molecular function of J-domain co-chaperones. Directly demonstrated biochemically. action: ACCEPT reason: The J domain stimulates HSP70 ATPase activity (PMID:12853476), making ATPase activator activity a core molecular function. supported_by: - reference_id: PMID:12853476 supporting_text: its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70 - term: id: GO:0001671 label: ATPase activator activity evidence_type: TAS original_reference_id: Reactome:R-HSA-5251959 qualifier: enables review: summary: Duplicate Reactome-sourced annotation of HSP70 ATPase stimulation by the J domain, a core molecular function of DNAJC7. action: ACCEPT reason: The J domain stimulates HSP70 ATPase activity (PMID:12853476); core molecular function. supported_by: - reference_id: PMID:12853476 supporting_text: its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70 - term: id: GO:0031072 label: heat shock protein binding evidence_type: IPI original_reference_id: PMID:12853476 qualifier: enables review: summary: DNAJC7 binds the heat shock proteins HSP70 and HSP90 directly through its TPR domains, the structural basis for its co-chaperone bridging function. action: ACCEPT reason: Direct, experimentally documented binding of HSP70 and HSP90 via the TPR domains is central to DNAJC7's function. supported_by: - reference_id: PMID:12853476 supporting_text: Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: High-throughput proteomics detection in a membrane fraction. DNAJC7 is a soluble cytoplasmic/nuclear co-chaperone with no membrane-spanning region. action: MARK_AS_OVER_ANNOTATED reason: Membrane localization from a high-throughput proteomics dataset is inconsistent with the soluble nature of DNAJC7 and likely reflects fractionation carryover. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888 - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-5251955 qualifier: located_in review: summary: Reactome pathway-curated nucleoplasmic localization, consistent with the documented nuclear pool of DNAJC7. action: KEEP_AS_NON_CORE reason: Nucleoplasmic localization is genuine but secondary to the core cytoplasmic function. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:11573955}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5251959 qualifier: located_in review: summary: Reactome pathway-curated cytosolic localization, the primary compartment of DNAJC7 action. action: ACCEPT reason: Cytosol is the principal, experimentally supported site of DNAJC7's co-chaperone activity. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: High-throughput exosome proteomics detection. DNAJC7 is a cytoplasmic/nuclear co-chaperone; exosomal detection does not reflect its core localization or function. action: MARK_AS_OVER_ANNOTATED reason: Detection in an exosome proteomics dataset is peripheral and likely reflects passive incorporation of abundant cytosolic chaperome proteins. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-goa.tsv supporting_text: GO:0070062 extracellular exosome cellular_component ECO:0007005 HDA PMID:19056867 - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:12853476 qualifier: located_in review: summary: Direct experimental evidence for cytoplasmic localization, the primary site where DNAJC7 acts as an HSP70/HSP90 co-chaperone. action: ACCEPT reason: Cytoplasm is the experimentally supported principal compartment of DNAJC7. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0006457 label: protein folding evidence_type: IDA original_reference_id: PMID:12853476 qualifier: involved_in review: summary: DNAJC7 participates in chaperone-mediated folding of clients (e.g. the glucocorticoid receptor) by regulating the HSP70/HSP90 system. It does not autonomously fold clients; folding is the downstream process outcome of its co-chaperone activity. action: KEEP_AS_NON_CORE reason: Protein folding is a downstream biological-process consequence of DNAJC7's co-chaperone role; as a co-chaperone it assists rather than catalyzes folding. supported_by: - reference_id: PMID:12853476 supporting_text: Hsp70 and Hsp90 cooperate with various co-chaperone proteins in the folding of a growing set of substrates, including the glucocorticoid receptor - term: id: GO:0006457 label: protein folding evidence_type: IDA original_reference_id: PMID:18620420 qualifier: involved_in review: summary: DNAJC7 supports Hsp90-dependent chaperoning/folding of clients such as the progesterone receptor and the kinase CHK1, substituting for type I/II J proteins. A downstream process outcome of its co-chaperone activity. action: KEEP_AS_NON_CORE reason: Protein folding is a downstream consequence of DNAJC7's co-chaperone activity rather than its direct molecular function. supported_by: - reference_id: PMID:18620420 supporting_text: Tpr2 replaced type I and II J proteins in the Hsp90-dependent chaperoning of the PR and the protein kinase, Chk1 - term: id: GO:0006457 label: protein folding evidence_type: TAS original_reference_id: PMID:8836031 qualifier: involved_in review: summary: Early characterization annotating DNAJC7/TPR2 to protein folding. Consistent with its co-chaperone role; folding is the downstream process outcome. action: KEEP_AS_NON_CORE reason: Protein folding is a downstream biological-process consequence of the co-chaperone role; non-core relative to the molecular co-chaperone function. supported_by: - reference_id: file:human/DNAJC7/DNAJC7-uniprot.txt supporting_text: Acts as a co-chaperone regulating the molecular chaperones HSP70 and HSP90 in folding of steroid receptors references: - id: GO_REF:0000044 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: PMID:11573955 title: The J domain of Tpr2 regulates its interaction with the proapoptotic and cell-cycle checkpoint protein, Rad9. findings: - statement: DNAJC7/Tpr2 interacts with the 9-1-1 checkpoint clamp components RAD9A, HUS1 and RAD1 and localizes to both cytoplasm and nucleus; the J domain regulates the RAD9A interaction and subcellular distribution. reference_section_type: RESULTS - id: PMID:12853476 title: Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Cached publication (publications/PMID_12853476.md) PubMed title matches the YAML title exactly; abstract states Tpr2/DNAJC7 recognizes both Hsp70 and Hsp90 via its TPR domains and that its J domain stimulates Hsp70 ATP hydrolysis, directly supporting the J-domain Hsp70-ATPase-stimulation and dual-TPR Hsp70/Hsp90-binding core functions (cited in core_functions)." findings: - statement: Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains, and its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70. reference_section_type: ABSTRACT - statement: Tpr2 induces ATP-independent dissociation of Hsp90 (but not Hsp70) from chaperone-substrate complexes, mediating retrograde transfer of substrates from Hsp90 onto Hsp70. reference_section_type: ABSTRACT - id: PMID:17043677 title: 'Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia.' findings: [] - id: PMID:18620420 title: Role of the cochaperone Tpr2 in Hsp90 chaperoning. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Cached publication (publications/PMID_18620420.md) PubMed title matches the YAML title exactly; cached abstract states Tpr2 binds Hsp90 and Hsp70 simultaneously and can substitute for J proteins in Hsp90-dependent chaperoning of clients, supporting the dual-TPR Hsp70/Hsp90 co-chaperone core function (cited in core_functions). Full text not cached but abstract anchors the claim." findings: - statement: Tpr2 binds Hsp90 and Hsp70 simultaneously (like Hop) and can substitute for type I and II J proteins in the Hsp90-dependent chaperoning of the progesterone receptor and the protein kinase Chk1. reference_section_type: ABSTRACT - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: [] - id: PMID:19946888 title: Defining the membrane proteome of NK cells. findings: [] - id: PMID:22190034 title: Global landscape of HIV-human protein complexes. findings: [] - id: PMID:25036637 title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. findings: [] - id: PMID:26496610 title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances. findings: [] - id: PMID:31413325 title: HENA, heterogeneous network-based data set for Alzheimer's disease. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: [] - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: PMID:8836031 title: Identification and characterization of two novel tetratricopeptide repeat-containing genes. findings: [] - id: Reactome:R-HSA-3371453 title: Regulation of HSF1-mediated heat shock response findings: [] - id: Reactome:R-HSA-5251955 title: HSP70/HSP90 chaperone cycle (Reactome) findings: [] - id: Reactome:R-HSA-5251959 title: HSP70/HSP90 chaperone cycle (Reactome) findings: [] - id: file:human/DNAJC7/DNAJC7-uniprot.txt title: UniProt entry Q99615 (DNJC7_HUMAN), DnaJ homolog subfamily C member 7 / Tpr2 findings: - statement: Co-chaperone regulating HSP70 and HSP90 in folding of steroid receptors (GR, PR); proposed recycling chaperone facilitating return of substrates to early chaperoning; combines two TPR domains and a J domain; cytoplasmic and nuclear. reference_section_type: OTHER core_functions: - description: J-domain co-chaperone that stimulates the ATPase activity of HSP70, the catalytic basis for driving the HSP70 chaperone cycle. molecular_function: id: GO:0001671 label: ATPase activator activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:12853476 supporting_text: its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70 - description: Dual-TPR co-chaperone that binds the heat shock proteins HSP70 and HSP90 simultaneously, bridging and regulating the two chaperone machines and mediating retrograde transfer of substrates from HSP90 back onto HSP70. molecular_function: id: GO:0031072 label: heat shock protein binding locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:12853476 supporting_text: Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains - reference_id: PMID:18620420 supporting_text: Tpr2 can bind Hsp90 and Hsp70 simultaneously, which is also a property of the cochaperone Hop. proposed_new_terms: [] suggested_questions: - question: Do ALS-associated loss-of-function variants in DNAJC7 act primarily by impairing HSP70/HSP90 client recycling, and which neuronal client proteins (e.g. TDP-43) become destabilized as a result? - question: Is the retrograde HSP90-to-HSP70 substrate transfer activity unique to DNAJC7 among human J proteins, or shared with other TPR-containing co-chaperones? suggested_experiments: - description: Reconstitute the HSP70/HSP90 chaperone cycle in vitro with wild-type versus ALS-mutant DNAJC7 and measure HSP70 ATPase stimulation, simultaneous HSP70/HSP90 binding, and substrate handoff using a model client (GR or CHK1). - description: CRISPR knockout of DNAJC7 in neurons followed by proteomics to identify destabilized clients and assess effects on TDP-43 solubility and HSF1-mediated stress responses.