DNAJC7

UniProt ID: Q99615
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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.

Existing Annotations Review

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

Core Functions

J-domain co-chaperone that stimulates the ATPase activity of HSP70, the catalytic basis for driving the HSP70 chaperone cycle.

Molecular Function:
ATPase activator activity
Cellular Locations:
cytoplasm
Supporting Evidence:
  • PMID:12853476
    its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70

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:
heat shock protein binding
Cellular Locations:
cytoplasm
Supporting Evidence:
  • PMID:12853476
    Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains
  • PMID:18620420
    Tpr2 can bind Hsp90 and Hsp70 simultaneously, which is also a property of the cochaperone Hop.

References

GO_REF:0000044
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
PMID:11573955
The J domain of Tpr2 regulates its interaction with the proapoptotic and cell-cycle checkpoint protein, Rad9.
  • 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.
PMID:12853476
Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system.
  • Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains, and its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70.
  • Tpr2 induces ATP-independent dissociation of Hsp90 (but not Hsp70) from chaperone-substrate complexes, mediating retrograde transfer of substrates from Hsp90 onto Hsp70.
PMID:17043677
Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia.
PMID:18620420
Role of the cochaperone Tpr2 in Hsp90 chaperoning.
  • 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.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:22190034
Global landscape of HIV-human protein complexes.
PMID:25036637
A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
PMID:26496610
A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
PMID:31413325
HENA, heterogeneous network-based data set for Alzheimer's disease.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
PMID:8836031
Identification and characterization of two novel tetratricopeptide repeat-containing genes.
Reactome:R-HSA-3371453
Regulation of HSF1-mediated heat shock response
Reactome:R-HSA-5251955
HSP70/HSP90 chaperone cycle (Reactome)
Reactome:R-HSA-5251959
HSP70/HSP90 chaperone cycle (Reactome)
file:human/DNAJC7/DNAJC7-uniprot.txt
UniProt entry Q99615 (DNJC7_HUMAN), DnaJ homolog subfamily C member 7 / Tpr2
  • 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.

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(DNAJC7-notes.md)

DNAJC7 (Tpr2 / TTC2) research notes

Identity

  • UniProt Q99615 (DNJC7_HUMAN), 494 aa. HGNC:12392. Synonyms TPR2, TTC2.
  • Domain architecture: 9 TPR repeats (two TPR clusters) + a C-terminal J domain (DOMAIN 381..451)
    [file:human/DNAJC7/DNAJC7-uniprot.txt FT DOMAIN J / REPEAT TPR 1..9]. This is the classic
    "type III J protein" plus dual TPR domain architecture.

Core molecular function

  • Co-chaperone that bridges/regulates HSP70 and HSP90 chaperone machines.
    PMID:12853476 -> J-domain stimulates Hsp70 ATPase
    = ATPase activator activity (GO:0001671); TPR domains bind Hsp70 and Hsp90 = heat shock protein binding.
  • Mechanism: mediates retrograde transfer of substrates from Hsp90 back onto Hsp70 ("recycling chaperone").
    PMID:12853476
  • Required at a narrowly defined expression level for GR activation PMID:12853476
  • Binds Hsp90 and Hsp70 simultaneously, like Hop, but with distinct ATP-dependence; can substitute for
    type I/II J proteins in Hsp90-dependent chaperoning of PR and the kinase Chk1.
    [PMID:18620420 "Tpr2 can bind Hsp90 and Hsp70 simultaneously, which is also a property of the cochaperone
    Hop." ; "Tpr2 replaced type I and II J proteins in the Hsp90-dependent chaperoning of the PR and the
    protein kinase, Chk1."]
  • UniProt FUNCTION: "Acts as a co-chaperone regulating the molecular chaperones HSP70 and HSP90 in folding
    of steroid receptors, such as the glucocorticoid receptor and the progesterone receptor. Proposed to act
    as a recycling chaperone by facilitating the return of chaperone substrates to early stages of chaperoning
    if further folding is required." [file:human/DNAJC7/DNAJC7-uniprot.txt]

Interactions (UniProt SUBUNIT)

  • HSP90AA1, HSP90AB1, HSPA1A/B (ATP-enhanced), HSPA8 (Hsc70), PGR, NR1I3/CAR (recruits to cytoplasm),
    RAD9A/HUS1/RAD1 (9-1-1 checkpoint clamp), NF1 GAP domain.
  • Mutagenesis: R101A and R333A impair Hsp90/Hsp70 binding; H409A (J-domain HPD) -> predominantly nuclear,
    abolishes interaction when combined. [file:human/DNAJC7/DNAJC7-uniprot.txt FT MUTAGEN]
  • IntAct hits (bare protein binding in GOA): BAG2 (O95816), BAG4 (O95429), DISC1 (Q9NRI5), HSPA1L (P34931),
    MLF2 (Q15773), HIV vif (P12504, xeno). These map the GOA IPI rows.

Localization

  • Cytoplasm (IDA PMID:12853476), Nucleus (EXP PMID:11573955; H409A mutant predominantly nuclear),
    cytoskeleton/microtubules (by similarity; colocalizes with NR1I3). Extracellular exosome and membrane
    are high-throughput proteomics (HDA) — non-core.

Disease

  • DNAJC7 is an ALS risk gene: rare/loss-of-function variants in DNAJC7 cause familial and sporadic ALS,
    first implicated by exome sequencing (Farhan et al. 2019, Nat Neurosci). Recent work links DNAJC7 to
    neuroprotection against proteotoxic stress via modulating HSF1 activity, and biallelic LoF variants cause
    familial ALS with TDP-43 pathology. (Established background; not in cached pubs — not quoted as supporting_text.)

GOA review logic

  • ATPase activator activity (GO:0001671, TAS Reactome): ACCEPT, CORE — J domain stimulates Hsp70 ATPase.
  • heat shock protein binding (GO:0031072, IPI): ACCEPT, CORE — binds Hsp70/Hsp90 directly.
  • protein folding (GO:0006457, IDA x2 + TAS): KEEP_AS_NON_CORE — co-chaperone assists folding, downstream BP.
  • regulation of cellular response to heat (GO:1900034, TAS Reactome): KEEP_AS_NON_CORE — HSF1/HSR pathway role.
  • Localization: cytoplasm/cytosol (IDA/EXP) ACCEPT; nucleus/nucleoplasm (EXP/IDA) KEEP_AS_NON_CORE (genuine
    but secondary, J-domain-regulated); cytoskeleton (IEA) KEEP_AS_NON_CORE; membrane/extracellular exosome
    (HDA) MARK_AS_OVER_ANNOTATED (proteomics carryover).
  • protein binding (GO:0005515, IPI x8): bare term, KEEP_AS_NON_CORE (real interactions, uninformative term).

Pn Notes

(DNAJC7-pn-notes.md)

DNAJC7 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q99615
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07b
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • 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.
  • Existing/core annotation action counts: ACCEPT: 8; KEEP_AS_NON_CORE: 17; MARK_AS_OVER_ANNOTATED: 2

PN Consistency Summary

  • Consistency: Fully consistent and the most richly supported of the set. Deep research (notes), review and PN converge on DNAJC7/Tpr2: dual TPR clusters + C-terminal J domain that binds HSP70 and HSP90 simultaneously and, via its J domain, stimulates HSP70 ATPase, mediating retrograde HSP90→HSP70 substrate transfer (PMID:12853476 VERIFIED, 18620420 VERIFIED); ALS risk gene. Review core MFs are GO:0001671 ATPase activator activity and GO:0031072 heat shock protein binding (both ACCEPT) — exactly matching PN row2's GO:0031072 (already_in_goa_exact, confirmed in GOA). PN row1 additionally projects GO:0030544 Hsp70 protein binding (narrower); GOA has the parent GO:0031072 but not GO:0030544.
  • PN story / NEW pressure: Row2 already captured (GO:0031072 = review core MF, in GOA). Row1's GO:0030544 (verified real) is a more-specific ADD candidate: Tpr2's TPR domains bind both HSP70 and HSP90, so the broader GO:0031072 (which the review correctly chose for the dual HSP70/HSP90 binding) is arguably the better umbrella; GO:0030544 captures only the HSP70 arm. Defensible as a supplementary ADD but the existing GO:0031072 better reflects the joint HSP70/HSP90 cochaperone biology. The ATPase-activator MF (GO:0001671) is the strongest core call and is captured by the review but NOT projected by either PN node.
  • Evidence alignment: PN carries no row references. Review cites verified mechanistic literature (PMID:12853476, 18620420, 11573955, 8836031) + many HT IPI rows; no divergence from PN.
  • Verdict: Fully consistent; row2 already captured, row1 GO:0030544 a defensible-but-secondary more-specific ADD. Recommended edits: [MAP] note that for DNAJC7 the broader GO:0031072 (joint HSP70/HSP90 binding) is the better umbrella than the HSP70-only GO:0030544; consider also projecting the well-supported GO:0001671 ATPase activator activity (review core MF, in GOA) from the J-domain node.

Full Consistency Review

  • UniProt: Q99615 · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: two rows — row1 Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone; row2 Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone|CC-TPR and J domain containing (branch CY) ; PN-node mapping: row1 type → mapped/ok GO:0030544 Hsp70 protein binding (more_specific_than_existing_goa); row2 subtype → no_mapping, type → mapped/ok GO:0031072 heat shock protein binding (already_in_goa_exact); ancestors no_mapping.
  • Consistency: Fully consistent and the most richly supported of the set. Deep research (notes), review and PN converge on DNAJC7/Tpr2: dual TPR clusters + C-terminal J domain that binds HSP70 and HSP90 simultaneously and, via its J domain, stimulates HSP70 ATPase, mediating retrograde HSP90→HSP70 substrate transfer (PMID:12853476 VERIFIED, 18620420 VERIFIED); ALS risk gene. Review core MFs are GO:0001671 ATPase activator activity and GO:0031072 heat shock protein binding (both ACCEPT) — exactly matching PN row2's GO:0031072 (already_in_goa_exact, confirmed in GOA). PN row1 additionally projects GO:0030544 Hsp70 protein binding (narrower); GOA has the parent GO:0031072 but not GO:0030544.
  • PN story / NEW pressure: Row2 already captured (GO:0031072 = review core MF, in GOA). Row1's GO:0030544 (verified real) is a more-specific ADD candidate: Tpr2's TPR domains bind both HSP70 and HSP90, so the broader GO:0031072 (which the review correctly chose for the dual HSP70/HSP90 binding) is arguably the better umbrella; GO:0030544 captures only the HSP70 arm. Defensible as a supplementary ADD but the existing GO:0031072 better reflects the joint HSP70/HSP90 cochaperone biology. The ATPase-activator MF (GO:0001671) is the strongest core call and is captured by the review but NOT projected by either PN node.
  • Mapping strategy: Two-row treatment is correct (J-domain HSP70 system + HSP70-HSP90 integration). Neither node over-reaches. The PN's two-node split appropriately distinguishes the J-domain HSP70 role from the TPR-mediated HSP70/HSP90 bridging role.
  • Evidence alignment: PN carries no row references. Review cites verified mechanistic literature (PMID:12853476, 18620420, 11573955, 8836031) + many HT IPI rows; no divergence from PN.
  • Verdict: Fully consistent; row2 already captured, row1 GO:0030544 a defensible-but-secondary more-specific ADD. Recommended edits: [MAP] note that for DNAJC7 the broader GO:0031072 (joint HSP70/HSP90 binding) is the better umbrella than the HSP70-only GO:0030544; consider also projecting the well-supported GO:0001671 ATPase activator activity (review core MF, in GOA) from the J-domain node.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/DNAJC7/DNAJC7-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Cytonuclear proteostasis | Chaperone | HSP70 system | J-domain containing HSP70 cochaperone

  • UniProt: Q99615
  • In branches: CY
  • PN-node mapping records (path + ancestors):
    • [type] Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0030544 Hsp70 protein binding]
      rationale: In the PN hierarchy, this type denotes J-domain cochaperones assigned to the HSP70 system. Their shared mechanistic role is direct interaction with HSP70-family chaperones, making Hsp70 protein binding the most defensible GO target in the current cache.
    • [group] Cytonuclear proteostasis|Chaperone|HSP70 system
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [class] Cytonuclear proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [branch] Cytonuclear proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: Cytonuclear proteostasis | Chaperone | HSP70-HSP90 system integration | HSP70-HSP90 joint cochaperone | CC-TPR and J domain containing

  • UniProt: Q99615
  • In branches: CY
  • PN-node mapping records (path + ancestors):
    • [subtype] Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone|CC-TPR and J domain containing
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a family/domain/subtype label. It classifies PN members but is not itself a GO annotation target; any functional assertion should come from a parent role mapping or gene-specific review.
    • [type] Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0031072 heat shock protein binding]
      rationale: This PN type groups joint HSP70/HSP90 cochaperones. The shared mechanistic assertion is binding heat-shock-protein chaperones, while narrower domain labels remain non-mapping unless they carry an independent activity.
    • [group] Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [class] Cytonuclear proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [branch] Cytonuclear proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (2)

  • GO:0030544 Hsp70 protein binding | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone
  • GO:0031072 heat shock protein binding | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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.