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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. Reason: Nuclear localization is corroborated by experimental evidence (PMID:11573955) but is not where DNAJC7 performs its core HSP70/HSP90 co-chaperone function. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt Nucleus {ECO:0000269|PubMed:11573955}. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Automated transfer of cytoplasmic localization, consistent with the experimentally established cytoplasmic site where DNAJC7 acts as an HSP70/HSP90 co-chaperone. Reason: Cytoplasm is the primary, experimentally supported (PMID:12853476 IDA) compartment of DNAJC7 action. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Automated annotation of cytoskeletal localization, reflecting the by-similarity observation that DNAJC7 colocalizes with NR1I3 on microtubules. Reason: Cytoskeletal/microtubule association is a specialized context (NR1I3/CAR sequestration), peripheral to the core co-chaperone function. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt Cytoplasm, cytoskeleton {ECO:0000250|UniProtKB:Q9QYI3}. |
| GO:0005515 protein binding | IPI PMID:17043677 Disrupted in Schizophrenia 1 Interactome: evidence for the c... | KEEP AS NON CORE | Summary: High-throughput interaction (IntAct WITH DISC1, Q9NRI5). The bare protein binding term records a real interaction but is uninformative about function. Reason: Bare protein binding is uninformative per curation guidelines; retained as a recorded interaction, not elevated to core. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:17043677 UniProtKB:Q9NRI5 |
| GO:0005515 protein binding | IPI PMID:22190034 Global landscape of HIV-human protein complexes. | KEEP AS NON CORE | Summary: High-throughput interaction (IntAct WITH HIV-1 vif, P12504, xeno). Bare protein binding term; biologically peripheral viral-host interaction. Reason: Uninformative bare protein binding from a virus-host screen; not part of the core chaperone function. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:22190034 UniProtKB:P12504 |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | KEEP AS NON CORE | 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. Reason: Bare protein binding is uninformative; the informative chaperone-binding function is captured by the dedicated heat shock protein binding annotation. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25036637 UniProtKB:P34931 |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | KEEP AS NON CORE | Summary: High-throughput interaction (IntAct WITH BAG2, O95816). Bare protein binding term recording a co-chaperone interaction. Reason: Bare protein binding is uninformative; retained as a recorded interaction. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:26496610 UniProtKB:O95816 |
| GO:0005515 protein binding | IPI PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's d... | KEEP AS NON CORE | Summary: High-throughput interaction (IntAct WITH DISC1, Q9NRI5). Bare protein binding term. Reason: Bare protein binding is uninformative; retained as a recorded interaction. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:31413325 UniProtKB:Q9NRI5 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex affinity-purification interactome (Huttlin et al.) capturing a DNAJC7-BAG2 (O95816) interaction. Bare protein binding term. Reason: Bare protein binding is uninformative; retained as a recorded interaction. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:O95816 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | Summary: High-throughput interaction (IntAct WITH BAG4 O95429 and BAG2 O95816). Bare protein binding term recording co-chaperone interactions. Reason: Bare protein binding is uninformative; retained as a recorded interaction. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:35271311 UniProtKB:O95429 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-maps interactome capturing DNAJC7 interactions including BAG2 (O95816), HSPA1L (P34931) and MLF2 (Q15773). Bare protein binding term. Reason: Bare protein binding is uninformative; retained as a recorded interaction. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054 UniProtKB:O95816 |
| GO:1900034 regulation of cellular response to heat | TAS Reactome:R-HSA-3371453 | KEEP AS NON CORE | 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. Reason: Participation in the heat-shock response is a process-level consequence of the co-chaperone role rather than DNAJC7's direct molecular function. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:1900034 regulation of cellular response to heat biological_process ECO:0000304 TAS Reactome:R-HSA-3371453 |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence showing nucleoplasmic localization, consistent with the documented nuclear pool of DNAJC7. Reason: Nucleoplasmic localization is genuine but secondary to the cytoplasmic site of the core co-chaperone function. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt Nucleus {ECO:0000269|PubMed:11573955}. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence showing cytosolic localization, the primary compartment where DNAJC7 acts. Reason: Cytosol is the principal, experimentally supported site of DNAJC7's co-chaperone activity. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005634 nucleus | EXP PMID:11573955 The J domain of Tpr2 regulates its interaction with the proa... | KEEP AS NON CORE | Summary: Experimental evidence (interaction with the RAD9A checkpoint protein) for nuclear localization of DNAJC7. Genuine but secondary compartment. Reason: Nuclear localization is experimentally supported but peripheral to the core cytoplasmic co-chaperone function. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt Nucleus {ECO:0000269|PubMed:11573955}. |
| GO:0005737 cytoplasm | EXP PMID:11573955 The J domain of Tpr2 regulates its interaction with the proa... | ACCEPT | Summary: Experimental evidence for cytoplasmic localization of DNAJC7, its primary site of action. Reason: Cytoplasm is the experimentally supported principal compartment of DNAJC7. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0001671 ATPase activator activity | TAS Reactome:R-HSA-5251955 | ACCEPT | Summary: DNAJC7's J domain stimulates ATP hydrolysis by HSP70, the defining molecular function of J-domain co-chaperones. Directly demonstrated biochemically. Reason: The J domain stimulates HSP70 ATPase activity (PMID:12853476), making ATPase activator activity a core molecular function. Supporting Evidence: PMID:12853476 its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70 |
| GO:0001671 ATPase activator activity | TAS Reactome:R-HSA-5251959 | ACCEPT | Summary: Duplicate Reactome-sourced annotation of HSP70 ATPase stimulation by the J domain, a core molecular function of DNAJC7. Reason: The J domain stimulates HSP70 ATPase activity (PMID:12853476); core molecular function. Supporting Evidence: PMID:12853476 its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70 |
| GO:0031072 heat shock protein binding | IPI PMID:12853476 Cofactor Tpr2 combines two TPR domains and a J domain to reg... | ACCEPT | Summary: DNAJC7 binds the heat shock proteins HSP70 and HSP90 directly through its TPR domains, the structural basis for its co-chaperone bridging function. Reason: Direct, experimentally documented binding of HSP70 and HSP90 via the TPR domains is central to DNAJC7's function. Supporting Evidence: PMID:12853476 Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput proteomics detection in a membrane fraction. DNAJC7 is a soluble cytoplasmic/nuclear co-chaperone with no membrane-spanning region. Reason: Membrane localization from a high-throughput proteomics dataset is inconsistent with the soluble nature of DNAJC7 and likely reflects fractionation carryover. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5251955 | KEEP AS NON CORE | Summary: Reactome pathway-curated nucleoplasmic localization, consistent with the documented nuclear pool of DNAJC7. Reason: Nucleoplasmic localization is genuine but secondary to the core cytoplasmic function. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt Nucleus {ECO:0000269|PubMed:11573955}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5251959 | ACCEPT | Summary: Reactome pathway-curated cytosolic localization, the primary compartment of DNAJC7 action. Reason: Cytosol is the principal, experimentally supported site of DNAJC7's co-chaperone activity. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: High-throughput exosome proteomics detection. DNAJC7 is a cytoplasmic/nuclear co-chaperone; exosomal detection does not reflect its core localization or function. Reason: Detection in an exosome proteomics dataset is peripheral and likely reflects passive incorporation of abundant cytosolic chaperome proteins. Supporting Evidence: file:human/DNAJC7/DNAJC7-goa.tsv GO:0070062 extracellular exosome cellular_component ECO:0007005 HDA PMID:19056867 |
| GO:0005737 cytoplasm | IDA PMID:12853476 Cofactor Tpr2 combines two TPR domains and a J domain to reg... | ACCEPT | Summary: Direct experimental evidence for cytoplasmic localization, the primary site where DNAJC7 acts as an HSP70/HSP90 co-chaperone. Reason: Cytoplasm is the experimentally supported principal compartment of DNAJC7. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006457 protein folding | IDA PMID:12853476 Cofactor Tpr2 combines two TPR domains and a J domain to reg... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:12853476 Hsp70 and Hsp90 cooperate with various co-chaperone proteins in the folding of a growing set of substrates, including the glucocorticoid receptor |
| GO:0006457 protein folding | IDA PMID:18620420 Role of the cochaperone Tpr2 in Hsp90 chaperoning. | KEEP AS NON CORE | 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. Reason: Protein folding is a downstream consequence of DNAJC7's co-chaperone activity rather than its direct molecular function. Supporting Evidence: PMID:18620420 Tpr2 replaced type I and II J proteins in the Hsp90-dependent chaperoning of the PR and the protein kinase, Chk1 |
| GO:0006457 protein folding | TAS PMID:8836031 Identification and characterization of two novel tetratricop... | KEEP AS NON CORE | Summary: Early characterization annotating DNAJC7/TPR2 to protein folding. Consistent with its co-chaperone role; folding is the downstream process outcome. Reason: Protein folding is a downstream biological-process consequence of the co-chaperone role; non-core relative to the molecular co-chaperone function. Supporting Evidence: file:human/DNAJC7/DNAJC7-uniprot.txt Acts as a co-chaperone regulating the molecular chaperones HSP70 and HSP90 in folding of steroid receptors |
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Download this section (compressed HTML)Q: 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?
Q: Is the retrograde HSP90-to-HSP70 substrate transfer activity unique to DNAJC7 among human J proteins, or shared with other TPR-containing co-chaperones?
Experiment: 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).
Experiment: 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.
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