id: O60884
gene_symbol: DNAJA2
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DNAJA2 (DnaJ homolog subfamily A member 2) is a class I J-domain protein (HSP40
  co-chaperone) that functions as a co-chaperone for HSP70 family members. It contains
  an N-terminal J domain (with conserved HPD motif) that stimulates the ATPase activity
  of HSP70, a glycine/phenylalanine-rich region, a zinc-finger cysteine-rich domain
  (CR-type, with four CXXCXGXG repeats coordinating two zinc ions) involved in substrate
  recognition, and two C-terminal beta-barrel substrate-binding domains (CTDI and CTDII)
  plus a dimerization domain. DNAJA2 participates in the HSP70-mediated foldase pathway,
  delivering unfolded or misfolded protein substrates to HSP70 and stimulating ATP
  hydrolysis to promote productive protein refolding. It is farnesylated at Cys-409
  and localized to the cytosol and membranes. DNAJA2 works in combination with specific
  nucleotide exchange factors (NEFs) to generate functionally distinct HSP70 chaperone
  complexes. A key structural feature is that DNAJA2 reversibly self-assembles into
  highly ordered tubular oligomers (~200 angstrom width, D5 symmetry disks of five
  dimers) that can dissociate into active dimers; this self-association equilibrium
  is temperature-sensitive (heat shock at 40 degrees C promotes dissociation with
  t1/2 ~2.3 min) and regulates its client-binding ("holding") activity and productive
  interaction with Hsc70 (DOI:10.1038/s41467-023-41150-8). Beyond general protein
  refolding, DNAJA2 functions as a client-selective Hsc70 co-chaperone that can bias
  quality-control decisions toward degradation through ERAD (e.g., CFTR with CHIP,
  DOI:10.1371/journal.pone.0220984) or chaperone-mediated autophagy (CMA) of specific
  substrates such as PCM1/CEP290 at centrosomes (DOI:10.1038/s41467-023-40952-0)
  and CSB during transcription-coupled nucleotide excision repair
  (DOI:10.1038/s41421-023-00601-8). DNAJA2 also potently suppresses tau amyloid
  formation in vitro by binding both monomeric tau and preformed fibrils through
  distinct C-terminal domains (DOI:10.7554/elife.69601).
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0005829 (cytosol) inferred from phylogenetic analysis across
      DnaJ subfamily A orthologs (including S. pombe, S. cerevisiae, and multiple mammalian
      orthologs). DNAJA2 cytosolic localization is well supported by multiple lines of
      evidence: IDA from Hageman et al. (PMID:21231916), Reactome pathway data placing
      DNAJA2 in cytosolic HSP70 chaperone complexes, and UniProt subcellular location
      indicating cytosolic and membrane association via farnesylation. The IBA annotation
      is consistent with all available data.
    action: ACCEPT
    reason: >-
      Cytosolic localization is core to DNAJA2 function as an HSP70 co-chaperone. This
      is confirmed by IDA evidence (PMID:21231916), Reactome pathway annotations, and
      UniProt records. The IBA phylogenetic inference is sound.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
          genes and most of the corresponding proteins are localized in the cytosol.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0001671 (ATPase activator activity) inferred from phylogenetic
      analysis across DnaJ family orthologs including yeast (Ydj1, Sis1, Xdj1) and
      C. elegans (dnj-12). Stimulation of HSP70 ATPase activity via the J domain is the
      defining biochemical function of all DnaJ/HSP40 proteins. For DNAJA2 specifically,
      Rauch and Gestwicki (PMID:24318877) demonstrated ATPase stimulation activity in vitro
      using purified components. UniProt confirms DNAJA2 stimulates ATP hydrolysis mediated
      by HSPA1A/B (PubMed:24318877). This is a core molecular function.
    action: ACCEPT
    reason: >-
      ATPase activator activity is the defining core molecular function of all J-domain
      proteins. DNAJA2 contains a canonical J domain and has been directly shown to
      stimulate HSP70 ATPase activity in vitro (PMID:24318877). The IBA inference is
      strongly supported by direct experimental evidence (IDA) from the same gene.
    supported_by:
      - reference_id: PMID:24318877
        supporting_text: >-
          we combined the Hsp70-NEF pairs with cochaperones of the J protein family
          (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The
          activity of the combinations in ATPase and luciferase refolding assays were
          dependent on the identity and stoichiometry of both the J protein and NEF so
          that some combinations were potent chaperones, whereas others were inactive.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0034605 (cellular response to heat) inferred from phylogenetic
      analysis including S. pombe (mas5/SPBC1734.11) and S. cerevisiae (Ydj1) orthologs.
      DnaJ/HSP40 proteins are classically associated with the heat shock response; they
      function as co-chaperones of HSP70 to handle heat-denatured proteins. Hageman et al.
      (PMID:21231916) demonstrated that DNAJA2 supports refolding of heat-denatured
      luciferase, confirming its role in the cellular response to heat stress. The term
      GO:0034605 (cellular response to heat) is more specific than GO:0009408 (response
      to heat) and is appropriate for DNAJA2 given its direct role in handling heat-denatured
      proteins.
    action: ACCEPT
    reason: >-
      DNAJA2 is an HSP40 co-chaperone that participates in the heat shock response pathway.
      Experimental evidence from Hageman et al. (PMID:21231916) directly demonstrates
      DNAJA2 supports refolding of heat-denatured substrates. The IBA inference from
      well-characterized yeast orthologs (Ydj1, mas5) is well supported.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          we assessed the effect of overexpression of each of these HSPs on refolding of
          heat-denatured luciferase and on the suppression of aggregation of a non-foldable
          polyQ (polyglutamine)-expanded Huntingtin fragment.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0042026 (protein refolding) inferred from phylogenetic analysis
      across DnaJ subfamily A orthologs including S. pombe (mas5), S. cerevisiae (Ydj1),
      DNAJA2 itself, and DNAJA4. Protein refolding is a core biological process of the
      HSP70/HSP40 foldase pathway. Hageman et al. (PMID:21231916) directly demonstrated
      that DNAJA2 supports luciferase refolding after heat denaturation. Rauch and
      Gestwicki (PMID:24318877) showed that DnaJA2 in combination with Hsp72 and NEFs
      promotes luciferase refolding in vitro. This is a core function of DNAJA2.
    action: ACCEPT
    reason: >-
      Protein refolding is a core biological process function of DNAJA2 as an HSP70
      co-chaperone. Directly demonstrated by IDA evidence (PMID:21231916) and confirmed
      by in vitro reconstitution experiments (PMID:24318877). The IBA phylogenetic
      inference from yeast and mammalian orthologs is well supported.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Overexpressed chaperones that suppressed polyQ aggregation were found not to be
          able to stimulate luciferase refolding. Inversely, chaperones that supported
          luciferase refolding were poor suppressors of polyQ aggregation.
      - reference_id: PMID:24318877
        supporting_text: >-
          we combined the Hsp70-NEF pairs with cochaperones of the J protein family
          (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The
          activity of the combinations in ATPase and luciferase refolding assays were
          dependent on the identity and stoichiometry of both the J protein and NEF so
          that some combinations were potent chaperones, whereas others were inactive.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962)
      because it conflates the binding aspect with the functional chaperone activity.
      DNAJA2 is a class I J-domain protein that functions as a co-chaperone in the
      HSP70 foldase pathway. It binds unfolded substrates and delivers them to HSP70
      for productive refolding, rather than simply binding unfolded proteins passively.
      Hageman et al. (PMID:21231916) showed that overexpression of class A J-domain
      proteins including DNAJA2 supported luciferase refolding, and Rauch and Gestwicki
      (PMID:24318877) demonstrated that DnaJA2 promoted refolding in combination with
      Hsp72. The correct replacement is GO:0044183 (protein folding chaperone), which
      captures the active role of DNAJA2 in assisting protein folding as a co-chaperone.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted per go-ontology#30962. DNAJA2 does not simply bind
      unfolded proteins; it actively participates in the HSP70-mediated foldase pathway
      by delivering substrates and stimulating ATP hydrolysis. GO:0044183 (protein
      folding chaperone) is the appropriate replacement, defined as binding to a protein
      or protein-containing complex to assist the protein folding process. This
      accurately describes DNAJA2's co-chaperone function with HSP70.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    additional_reference_ids:
      - PMID:21231916
      - PMID:24318877
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Overexpressed chaperones that suppressed polyQ aggregation were found not to
          be able to stimulate luciferase refolding. Inversely, chaperones that
          supported luciferase refolding were poor suppressors of polyQ aggregation.
      - reference_id: PMID:24318877
        supporting_text: >-
          we combined the Hsp70-NEF pairs with cochaperones of the J protein family
          (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The
          activity of the combinations in ATPase and luciferase refolding assays were
          dependent on the identity and stoichiometry of both the J protein and NEF so
          that some combinations were potent chaperones, whereas others were inactive.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0051087 (protein-folding chaperone binding) inferred from
      phylogenetic analysis including DNAJA2 itself, DNAJA1 (P31689), and DNAJA4 (Q8WW22).
      DNAJA2 directly binds HSP70 family members (HSPA1A/B, HSPA8, HSPA6) via its
      J domain, which is the core mechanism for stimulating HSP70 ATPase activity and
      delivering substrates. Hageman et al. (PMID:21231916) demonstrated physical
      interaction between DNAJA2 and multiple HSP70 isoforms. This accurately captures
      the co-chaperone binding relationship.
    action: ACCEPT
    reason: >-
      Protein-folding chaperone binding is a core molecular function of DNAJA2.
      As a J-domain protein, DNAJA2 physically binds HSP70 chaperones to stimulate their
      ATPase activity and deliver substrates. IPI evidence from PMID:21231916 documents
      interactions with HSPA1A/B and HSPA6. The IBA inference is well supported.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
          genes and most of the corresponding proteins are localized in the cytosol.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation of GO:0001671 (ATPase activator activity) from ARBA machine learning
      models. This is consistent with the IBA and IDA annotations for the same term.
      DNAJA2 stimulates HSP70 ATPase activity via its J domain, as directly demonstrated
      by Rauch and Gestwicki (PMID:24318877). The ARBA prediction is correct.
    action: ACCEPT
    reason: >-
      The IEA annotation is concordant with both IBA (GO_REF:0000033) and IDA
      (PMID:24318877) evidence for the same term. ATPase activator activity is a core
      molecular function of DNAJA2.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation of GO:0005524 (ATP binding) inferred from InterPro domain IPR012724
      (DnaJ). While DnaJ proteins interact with the HSP70 ATPase cycle, DnaJ/HSP40
      proteins themselves do not bind ATP directly. The J domain stimulates the ATPase
      activity of HSP70, but it is HSP70 that binds and hydrolyzes ATP. DNAJA2 does not
      have its own ATPase domain or ATP binding site. This IEA annotation appears to be
      an artifact of the broad InterPro-to-GO mapping for the DnaJ family, which may
      conflate the ATP-dependent cycle of the HSP70 partner with ATP binding by the
      J-domain protein itself.
    action: REMOVE
    reason: >-
      DnaJ/HSP40 co-chaperones do not bind ATP themselves. They stimulate the ATPase
      activity of HSP70 proteins, but it is the HSP70 partner (e.g., HSPA1A/B) that
      binds and hydrolyzes ATP. DNAJA2 has no known ATP binding site. The InterPro
      mapping from IPR012724 (DnaJ) to GO:0005524 (ATP binding) is misleading for
      this protein family. UniProt does not annotate DNAJA2 with ATP binding activity.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation of GO:0006457 (protein folding) inferred from combined automated
      methods (ARBA and InterPro domains IPR008971, IPR012724, IPR044713). DNAJA2
      participates in protein folding as a co-chaperone in the HSP70 foldase pathway.
      The more specific child term GO:0042026 (protein refolding) is annotated by both
      IBA and IDA evidence. GO:0006457 is the broader parent term and is acceptable
      as a general IEA annotation, even though the more specific term exists from
      higher-quality evidence.
    action: ACCEPT
    reason: >-
      Protein folding is a legitimate biological process annotation for DNAJA2 as an
      HSP70 co-chaperone. While GO:0042026 (protein refolding) is the more specific
      term supported by IBA and IDA, the broader GO:0006457 from IEA is acceptable
      and not incorrect. DNAJA2 participates in both de novo folding and refolding
      pathways via its HSP70 co-chaperone function.
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation of GO:0008270 (zinc ion binding) inferred from UniProtKB keyword
      KW-0863 (Zinc). DNAJA2 contains a CR-type zinc finger domain (residues 130-214)
      with four CXXCXGXG repeat motifs that coordinate two zinc ions through eight
      cysteine residues. The zinc finger domain is a defining feature of class I (type A)
      DnaJ proteins and is involved in substrate recognition and binding. UniProt annotates
      eight zinc-binding cysteine residues (by similarity). This is a structural feature
      integral to DNAJA2 function.
    action: ACCEPT
    reason: >-
      Zinc ion binding is a well-established structural feature of DNAJA2. The CR-type
      zinc finger domain with four CXXCXGXG repeats coordinates two zinc ions and is
      required for substrate binding function. UniProt documents eight zinc-binding
      residues. This is a core structural property of class I DnaJ proteins.
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation of GO:0009408 (response to heat) inferred from InterPro domain
      IPR012724 (DnaJ). This is the broader parent term of GO:0034605 (cellular response
      to heat) which is annotated by IBA. DnaJ proteins are heat shock proteins that
      function in the cellular response to heat stress. The IEA annotation is consistent
      with but less specific than the IBA annotation for GO:0034605. It is acceptable
      as a broader IEA.
    action: ACCEPT
    reason: >-
      Response to heat is a legitimate biological process for DNAJA2 as an HSP40
      co-chaperone. The more specific GO:0034605 (cellular response to heat) is
      annotated by IBA. The IEA annotation of the broader parent term GO:0009408 is
      acceptable and consistent.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation of GO:0016020 (membrane) inferred from UniProtKB subcellular
      location vocabulary mapping. UniProt annotates DNAJA2 subcellular location as
      "Membrane; Lipid-anchor" based on its farnesylation at Cys-409 (PMID:15308774).
      The C-terminal CAHQ motif undergoes farnesylation, proteolytic processing, and
      carboxymethylation, tethering the mature protein to membranes. This is a legitimate
      secondary localization for DNAJA2, though the primary localization is cytosolic.
    action: ACCEPT
    reason: >-
      Membrane association via farnesylation at Cys-409 is experimentally confirmed
      (PMID:15308774). UniProt annotates DNAJA2 as lipid-anchored to membranes. While
      the primary localization is cytosolic, membrane association is a real secondary
      localization.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation of GO:0030544 (Hsp70 protein binding) inferred from InterPro domain
      IPR044713 (DNJA1/2-like). DNAJA2 directly binds HSP70 proteins via its J domain,
      as demonstrated by Hageman et al. (PMID:21231916) who showed physical interaction
      with HSPA1A/B and HSPA6, and by Rauch and Gestwicki (PMID:24318877) who used
      purified DNAJA2 with Hsp72. However, GO:0030544 is a child of GO:0005515 (protein
      binding) and essentially captures the binding aspect only. The more informative
      term GO:0051087 (protein-folding chaperone binding) is already annotated and better
      captures the functional context. Nevertheless, GO:0030544 is more specific than
      generic protein binding and is technically correct.
    action: ACCEPT
    reason: >-
      Hsp70 protein binding is experimentally demonstrated for DNAJA2 (PMID:21231916,
      PMID:24318877). The InterPro mapping from IPR044713 is correct. While GO:0051087
      (protein-folding chaperone binding) is also annotated and captures the functional
      context, GO:0030544 specifically captures the HSP70-binding aspect and is
      technically accurate.
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation of GO:0031072 (heat shock protein binding) inferred from InterPro
      domain IPR001305 (HSP DnaJ cysteine-rich domain). This is a parent term of
      GO:0030544 (Hsp70 protein binding) which is also annotated. DNAJA2 binds HSP70
      family members, so this broader term is technically correct but redundant with the
      more specific GO:0030544. As an IEA it is acceptable to have both the general
      and specific terms.
    action: ACCEPT
    reason: >-
      Heat shock protein binding is correct for DNAJA2 as it binds HSP70 chaperones.
      The more specific GO:0030544 (Hsp70 protein binding) is also annotated from IEA.
      The broader IEA is acceptable and not incorrect.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation of GO:0046872 (metal ion binding) inferred from UniProtKB keyword
      KW-0479 (Metal-binding). This is the broader parent of GO:0008270 (zinc ion
      binding) which is also annotated by IEA. DNAJA2 coordinates two zinc ions in its
      CR-type zinc finger domain. The generic metal ion binding term is technically
      correct but less informative than the specific zinc ion binding term.
    action: ACCEPT
    reason: >-
      Metal ion binding is correct for DNAJA2 as it binds zinc ions in its cysteine-rich
      domain. The more specific GO:0008270 (zinc ion binding) is also annotated. As an
      IEA annotation of the broader parent term it is acceptable.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation of GO:0051082 (unfolded protein binding) inferred from InterPro
      domain matches (IPR001305 cysteine-rich domain, IPR008971 HSP40/DnaJ peptide-
      binding domain, IPR012724 DnaJ). GO:0051082 is being obsoleted per
      go-ontology#30962 because it conflates passive binding with active chaperone
      function. DNAJA2 is a class I J-domain protein / HSP40 co-chaperone that
      actively assists protein folding through the HSP70 foldase pathway, not merely
      binding unfolded proteins. The InterPro domains correctly identify DNAJA2 as a
      DnaJ family member with substrate-binding capacity, but the appropriate
      molecular function term is GO:0044183 (protein folding chaperone).
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted per go-ontology#30962. The InterPro-based
      inference correctly identifies DNAJA2 as having DnaJ domains with substrate
      binding capacity, but the term conflates binding with the active chaperone
      function. DNAJA2 functions as a protein folding chaperone in the HSP70 foldase
      pathway. GO:0044183 (protein folding chaperone) is the correct replacement.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation of GO:0051087 (protein-folding chaperone binding) from ARBA machine
      learning models. This is concordant with IBA (GO_REF:0000033) and IPI
      (PMID:21231916) annotations for the same term. DNAJA2 binds HSP70 chaperones via
      its J domain. The ARBA prediction is correct.
    action: ACCEPT
    reason: >-
      The IEA annotation is concordant with IBA and IPI evidence for the same term.
      Protein-folding chaperone binding is a core molecular function of DNAJA2 as an
      HSP70 co-chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22085931
  review:
    summary: >-
      IPI annotation of GO:0005515 (protein binding) based on interaction with AICDA
      (Q9GZX7, activation-induced cytidine deaminase) from Orthwein et al.
      (PMID:22085931). This study focused on the specific functional interaction between
      AID and DnaJa1, and explicitly showed that "both major cytoplasmic type I Hsp40s,
      DnaJa1 and DnaJa2, are induced upon B-cell activation and interact with AID in
      vitro, only DnaJa1 overexpression increases AID levels and biological activity in
      cell lines." Thus DNAJA2 interacts with AID but does NOT functionally stabilize it
      (that is DNAJA1-specific). The interaction is real but the generic protein binding
      term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The study specifically demonstrates that while DNAJA2 can interact with AID in
      vitro, the functional interaction is specific to DNAJA1, not DNAJA2. The generic
      protein binding term does not convey this important distinction. The interaction
      with AID appears to lack functional consequence for DNAJA2.
    supported_by:
      - reference_id: PMID:22085931
        supporting_text: >-
          Although both major cytoplasmic type I Hsp40s, DnaJa1 and DnaJa2, are induced
          upon B-cell activation and interact with AID in vitro, only DnaJa1
          overexpression increases AID levels and biological activity in cell lines.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  review:
    summary: >-
      IPI annotation of GO:0005515 (protein binding) from Taipale et al. (PMID:25036637),
      a large-scale systematic chaperone interaction network study. Interacting partners
      are DNAJA4 (Q8WW22) and NUDC (Q9Y266). DNAJA4 interaction represents homo-/hetero-
      oligomeric interactions among DnaJ family members, which is expected. NUDC
      interaction is notable as NUDC family cochaperones specifically associate with
      beta-propeller folds per this study. However, the generic GO:0005515 term is
      uninformative for a co-chaperone that interacts with many proteins as part of its
      chaperone function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) is uninformative for DNAJA2, which is a co-chaperone
      that by definition interacts with many proteins. The specific interactions from
      this study (DNAJA4, NUDC) are part of the chaperone interaction network but the
      generic term does not capture any specific functional insight.
    supported_by:
      - reference_id: PMID:25036637
        supporting_text: >-
          We have combined mass spectrometry and quantitative high-throughput LUMIER
          assays to systematically characterize the chaperone/co-chaperone/client
          interaction network in human cells. We uncover hundreds of novel chaperone
          clients, delineate their participation in specific co-chaperone complexes, and
          establish a surprisingly distinct network of protein/protein interactions for
          co-chaperones.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      IPI annotation of GO:0005515 (protein binding) from Luck et al. (PMID:32296183),
      the HuRI reference map of the human binary protein interactome. The interacting
      partner is DYNLT1 (P63172, dynein light chain Tctex-type 1). This is a large-scale
      Y2H interaction screen. The interaction with DYNLT1 is also documented in IntAct
      with 3 experiments (per UniProt). While the interaction may be real, the generic
      protein binding term is uninformative for a co-chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) is uninformative for DNAJA2. The specific interaction
      with DYNLT1 from the HuRI large-scale screen may reflect a chaperone-client
      relationship rather than a functional partnership, and the generic term does not
      capture any meaningful functional insight.
    supported_by:
      - reference_id: PMID:32296183
        supporting_text: >-
          Here we present a human 'all-by-all' reference interactome map of human binary
          protein interactions, or 'HuRI'. With approximately 53,000 protein-protein
          interactions, HuRI has approximately four times as many such interactions as
          there are high-quality curated interactions from small-scale studies.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      IPI annotation of GO:0005515 (protein binding) from Huttlin et al. (PMID:33961781),
      the BioPlex 3.0 proteome-scale network. Interacting partners are DCAF10 (Q5QP82),
      DNAJA4 (Q8WW22), and NUDC (Q9Y266). BioPlex uses AP-MS in 293T and HCT116 cells.
      The DNAJA4 and NUDC interactions are replicated across multiple studies
      (PMID:25036637, PMID:40205054). Generic protein binding is uninformative for a
      co-chaperone that by nature interacts with many cellular proteins.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) is uninformative for DNAJA2. While the AP-MS
      interactions are high-quality, the generic term does not capture the co-chaperone
      functional context. The DNAJA4 and NUDC interactions likely reflect co-chaperone
      network associations rather than informative functional insights beyond what is
      captured by GO:0051087 (protein-folding chaperone binding).
    supported_by:
      - reference_id: PMID:33961781
        supporting_text: >-
          Thousands of interactions assemble proteins into modules that impart spatial and
          functional organization to the cellular proteome. Through affinity-purification
          mass spectrometry, we have created two proteome-scale, cell-line-specific
          interaction networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: >-
      IPI annotation of GO:0005515 (protein binding) from Schaffer et al. (PMID:40205054),
      multimodal cell maps. Interacting partners are DCAF10 (Q5QP82), DNAJA4 (Q8WW22),
      and NUDC (Q9Y266), the same set as in BioPlex 3.0 (PMID:33961781). This replication
      across independent studies strengthens confidence in these interactions but the
      generic protein binding term remains uninformative for a co-chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) is uninformative for DNAJA2. These interactions are
      replicated from BioPlex 3.0 and reflect co-chaperone network topology. The generic
      term does not capture meaningful functional insight.
    supported_by:
      - reference_id: PMID:40205054
        supporting_text: >-
          Here we construct a global map of human subcellular architecture through joint
          measurement of biophysical interactions and immunofluorescence images for over
          5,100 proteins in U2OS osteosarcoma cells.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IPI annotation of GO:0051087 (protein-folding chaperone binding) based on Hageman
      et al. (PMID:21231916). The with/from column indicates interactions with HSPA1A
      (P0DMV8), HSPA1B (P0DMV9), and HSPA6 (P17066), all HSP70 family chaperones. This
      study systematically assessed HSP70/HSP40 functional interactions and demonstrated
      that DNAJA2 physically interacts with and functionally cooperates with multiple
      HSP70 isoforms in the foldase pathway. This is a core molecular function annotation
      that accurately captures DNAJA2's interaction with HSP70 chaperones.
    action: ACCEPT
    reason: >-
      Protein-folding chaperone binding is a core molecular function of DNAJA2. The IPI
      evidence from PMID:21231916 documents direct physical interaction with HSP70
      chaperones HSPA1A, HSPA1B, and HSPA6. This is a much more informative term than
      generic protein binding and accurately captures the co-chaperone binding function.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
          genes and most of the corresponding proteins are localized in the cytosol. To
          test for possible functional differences and/or substrate specificity, we
          assessed the effect of overexpression of each of these HSPs on refolding of
          heat-denatured luciferase and on the suppression of aggregation of a
          non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:24318877
  review:
    summary: >-
      IDA annotation of GO:0001671 (ATPase activator activity) based on Rauch and
      Gestwicki (PMID:24318877). This study directly measured DNAJA2's ability to
      stimulate ATPase activity of Hsp72 (HSPA1A) in vitro using purified recombinant
      proteins. DnaJA2 was combined with Hsp70-NEF pairs to generate 16 permutations,
      and ATPase activity was measured for each combination. UniProt confirms this
      function: "Stimulates ATP hydrolysis and the folding of unfolded proteins mediated
      by HSPA1A/B." This is the defining molecular function of all J-domain proteins
      and a core function of DNAJA2.
    action: ACCEPT
    reason: >-
      ATPase activator activity is the core molecular function of DNAJA2 as a J-domain
      protein. Directly demonstrated in vitro using purified components (PMID:24318877).
      Confirmed by UniProt functional description. This represents the strongest possible
      evidence type (IDA) for the most central function of this protein.
    supported_by:
      - reference_id: PMID:24318877
        supporting_text: >-
          we combined the Hsp70-NEF pairs with cochaperones of the J protein family
          (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The
          activity of the combinations in ATPase and luciferase refolding assays were
          dependent on the identity and stoichiometry of both the J protein and NEF so
          that some combinations were potent chaperones, whereas others were inactive.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371422
  review:
    summary: >-
      TAS annotation of GO:0005829 (cytosol) from Reactome pathway R-HSA-3371422 (ATP
      hydrolysis by HSP70). DNAJA2 is placed in the cytosol as part of the HSP70 chaperone
      cycle where J domain co-chaperones stimulate HSP70 ATPase activity. This is
      consistent with all other evidence for cytosolic localization.
    action: ACCEPT
    reason: >-
      Cytosolic localization is well established for DNAJA2. The Reactome pathway
      correctly places DNAJA2 in the cytosol for the HSP70 chaperone cycle. Concordant
      with IBA, IDA, and other TAS evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371503
  review:
    summary: >-
      TAS annotation of GO:0005829 (cytosol) from Reactome pathway R-HSA-3371503 (STIP1
      (HOP) binds HSP90 and HSP70:HSP40:nascent protein). DNAJA2 is placed in the cytosol
      as part of the HSP70:HSP40:nascent protein complex that is bridged to HSP90 by
      STIP1/HOP. Consistent with all other evidence for cytosolic localization.
    action: ACCEPT
    reason: >-
      Cytosolic localization is well established. The Reactome pathway places DNAJA2 in
      the HSP70-HSP90 client transfer pathway in the cytosol. Concordant with other
      evidence lines.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371590
  review:
    summary: >-
      TAS annotation of GO:0005829 (cytosol) from Reactome pathway R-HSA-3371590 (HSP70
      binds to HSP40:nascent protein). DNAJA2 is placed in the cytosol as the HSP40
      co-chaperone that first binds nascent/unfolded client proteins before delivering
      them to HSP70. Consistent with all other evidence.
    action: ACCEPT
    reason: >-
      Cytosolic localization is well established. The Reactome pathway correctly places
      DNAJA2 in the cytosol for the HSP70:HSP40 substrate delivery step. Concordant
      with IBA, IDA, and other TAS evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation of GO:0005829 (cytosol) based on Hageman et al. (PMID:21231916).
      This study assessed HSP70 and HSP40 family members, most of which are localized
      in the cytosol. DNAJA2 was shown to be cytosolic as part of the experimental
      characterization. This is the strongest evidence line for DNAJA2 cytosolic
      localization.
    action: ACCEPT
    reason: >-
      Cytosolic localization directly demonstrated (IDA) in the study by Hageman et al.
      This is concordant with IBA, TAS (Reactome), and IEA evidence. Cytosol is the
      primary subcellular localization for DNAJA2.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
          genes and most of the corresponding proteins are localized in the cytosol.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation of GO:0042026 (protein refolding) based on Hageman et al.
      (PMID:21231916). This study directly demonstrated that overexpression of DNAJA2
      supports refolding of heat-denatured luciferase, placing it in the HSP70-mediated
      foldase pathway. The study distinguished foldase activity (luciferase refolding)
      from holdase activity (polyQ aggregation suppression), and classified DnaJ subfamily
      A members as supporting the foldase pathway. This is a core biological process
      function of DNAJA2.
    action: ACCEPT
    reason: >-
      Protein refolding is directly demonstrated for DNAJA2 by the luciferase refolding
      assay (PMID:21231916). DNAJA2 participates in the HSP70-mediated foldase pathway.
      This is confirmed by in vitro reconstitution (PMID:24318877). Core biological
      process function.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          we assessed the effect of overexpression of each of these HSPs on refolding of
          heat-denatured luciferase and on the suppression of aggregation of a non-foldable
          polyQ (polyglutamine)-expanded Huntingtin fragment. Overexpressed chaperones
          that suppressed polyQ aggregation were found not to be able to stimulate
          luciferase refolding. Inversely, chaperones that supported luciferase refolding
          were poor suppressors of polyQ aggregation.
      - reference_id: PMID:24318877
        supporting_text: >-
          we combined the Hsp70-NEF pairs with cochaperones of the J protein family
          (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The
          activity of the combinations in ATPase and luciferase refolding assays were
          dependent on the identity and stoichiometry of both the J protein and NEF so
          that some combinations were potent chaperones, whereas others were inactive.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation of GO:0051082 (unfolded protein binding) based on Hageman et al.
      (PMID:21231916), which assessed functional differences among HSP70 and HSP40
      family members. The study tested overexpression of HSP70/HSPA and HSP40/DNAJ
      proteins on refolding of heat-denatured luciferase and suppression of polyQ
      aggregation. DNAJA2 was shown to participate in the foldase pathway, supporting
      luciferase refolding. GO:0051082 is being obsoleted per go-ontology#30962.
      DNAJA2 does not simply bind unfolded proteins passively; it functions as a
      co-chaperone in the HSP70-mediated protein folding pathway. UniProt describes
      DNAJA2 as a co-chaperone of Hsc70 that stimulates ATP hydrolysis and the folding
      of unfolded proteins mediated by HSPA1A/B. The correct replacement is GO:0044183
      (protein folding chaperone).
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted per go-ontology#30962. The experimental evidence
      from Hageman et al. (PMID:21231916) demonstrates that DNAJA2 functions in the
      HSP70-mediated foldase pathway, supporting luciferase refolding rather than
      merely binding unfolded proteins. UniProt confirms DNAJA2 is a co-chaperone of
      Hsc70 that stimulates ATP hydrolysis and folding. GO:0044183 (protein folding
      chaperone), defined as binding to a protein or protein-containing complex to
      assist the protein folding process, accurately captures this function.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    additional_reference_ids:
      - PMID:24318877
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          assessed the effect of overexpression of each of these HSPs on refolding of
          heat-denatured luciferase and on the suppression of aggregation of a
          non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment.
      - reference_id: PMID:24318877
        supporting_text: >-
          we combined the Hsp70-NEF pairs with cochaperones of the J protein family
          (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The
          activity of the combinations in ATPase and luciferase refolding assays were
          dependent on the identity and stoichiometry of both the J protein and NEF so
          that some combinations were potent chaperones, whereas others were inactive.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  review:
    summary: >-
      HDA annotation of GO:0070062 (extracellular exosome) based on Gonzales et al.
      (PMID:19056867), a large-scale proteomics study of urinary exosomes that identified
      1132 proteins. DNAJA2 was among the many proteins detected in urinary exosomes by
      LC-MS/MS. While this is a high-throughput proteomic detection, being found in
      exosomes is likely a consequence of the general abundance of cytosolic proteins
      in exosome preparations rather than a specific functional localization for DNAJA2.
      Exosome detection does not represent a core localization for this co-chaperone.
    action: KEEP_AS_NON_CORE
    reason: >-
      Detection in urinary exosomes via large-scale proteomics (PMID:19056867) is
      technically valid but represents a secondary observation rather than a core
      functional localization. Many abundant cytosolic proteins are detected in exosome
      preparations. DNAJA2's primary function is as a cytosolic HSP70 co-chaperone.
    supported_by:
      - reference_id: PMID:19056867
        supporting_text: >-
          Overall, the analysis identified 1132 proteins unambiguously, including 177
          that are represented on the Online Mendelian Inheritance in Man database of
          disease-related genes, suggesting that exosome analysis is a potential approach
          to discover urinary biomarkers
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: TAS
  original_reference_id: PMID:9383053
  review:
    summary: >-
      TAS annotation of GO:0008284 (positive regulation of cell population proliferation)
      based on Edwards et al. (PMID:9383053). This study identified human CPR (cell cycle
      progression restoration) genes that when overexpressed could overcome G1 arrest
      signals in yeast. DNAJA2 (then called CPR3) was one of 13 human genes identified
      in this screen. The study described CPR genes as representing "a variety of
      biochemical functions including a new cyclin, a tumor suppressor binding protein,
      chaperones, transcription factors, translation factors, RNA-binding proteins."
      However, the ability to overcome pheromone-induced G1 arrest in yeast when
      overexpressed does not directly demonstrate a role in positive regulation of cell
      proliferation in human cells. This is an indirect inference from a heterologous
      overexpression system, and likely reflects general chaperone activity facilitating
      cell cycle protein folding rather than a specific proliferation-regulatory function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The CPR screen (PMID:9383053) identified DNAJA2 as a gene that overcomes G1 arrest
      in yeast when overexpressed. This is a heterologous overexpression assay in yeast
      and does not demonstrate a specific role in positive regulation of cell proliferation
      in human cells. The effect is most likely attributable to general HSP40 chaperone
      activity assisting cell cycle protein homeostasis rather than a direct
      proliferation-regulatory function. No subsequent studies have established DNAJA2
      as a specific regulator of cell proliferation.
    supported_by:
      - reference_id: PMID:9383053
        supporting_text: >-
          We have identified 13 human CPR (cell cycle progression restoration) genes and
          11 yeast OPY (overproduction-induced pheromone-resistant yeast) genes that
          specifically block the G1 arrest by mating pheromone. The CPR genes represent
          a variety of biochemical functions including a new cyclin, a tumor suppressor
          binding protein, chaperones, transcription factors, translation factors,
          RNA-binding proteins, as well as novel proteins.
core_functions:
  - molecular_function:
      id: GO:0044183
      label: protein folding chaperone
    description: >-
      DNAJA2 is a class I J-domain co-chaperone (foldase-type) that delivers unfolded or
      misfolded protein substrates to HSP70 for productive ATP-dependent refolding. Its
      domain architecture includes an N-terminal J domain (HPD motif), a Gly/Phe-rich
      region, a zinc-finger cysteine-rich domain (four CXXCXGXG repeats coordinating two
      zinc ions) for substrate recognition, two C-terminal beta-barrel substrate-binding
      domains (CTDI and CTDII), and a dimerization domain. DNAJA2 reversibly self-assembles
      into highly ordered tubular oligomers (~200 angstrom width, D5 symmetry disks of
      five dimers) that serve as a storage form; heat shock (40 degrees C) drives rapid
      dissociation into active dimers (t1/2 ~2.3 min), and Hsc70 ATPase cycling coupled
      to J-domain interaction triggers oligomer disassembly
      (DOI:10.1038/s41467-023-41150-8). Beyond general protein refolding, DNAJA2 acts
      as a client-selective Hsc70 co-chaperone that can bias quality-control decisions
      toward degradation through ERAD (e.g., CFTR with Hsc70/CHIP,
      DOI:10.1371/journal.pone.0220984) or chaperone-mediated autophagy (CMA) of
      specific substrates such as PCM1/CEP290 at centrosomes
      (DOI:10.1038/s41467-023-40952-0) and CSB during TC-NER
      (DOI:10.1038/s41421-023-00601-8). DNAJA2 also potently suppresses tau amyloid
      formation using distinct CTDI (monomer-binding) and CTDII (fibril-binding)
      sites, achieving 88% reduction in fibril mass at sub-stoichiometric ratios
      (DOI:10.7554/elife.69601). DNAJA2 works in combination with specific nucleotide
      exchange factors (NEFs) to generate functionally distinct HSP70 chaperone complexes
      with varying foldase potency.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Overexpressed chaperones that suppressed polyQ aggregation were found not to
          be able to stimulate luciferase refolding. Inversely, chaperones that
          supported luciferase refolding were poor suppressors of polyQ aggregation.
      - reference_id: PMID:24318877
        supporting_text: >-
          we combined the Hsp70-NEF pairs with cochaperones of the J protein family
          (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The
          activity of the combinations in ATPase and luciferase refolding assays were
          dependent on the identity and stoichiometry of both the J protein and NEF so
          that some combinations were potent chaperones, whereas others were inactive.
    directly_involved_in:
      - id: GO:0042026
        label: protein refolding
      - id: GO:0006457
        label: protein folding
      - id: GO:0034605
        label: cellular response to heat
    locations:
      - id: GO:0005829
        label: cytosol
  - molecular_function:
      id: GO:0001671
      label: ATPase activator activity
    description: >-
      DNAJA2 stimulates the intrinsic ATPase activity of HSP70 (HSPA1A/B, HSPA8/Hsc70)
      through its conserved J-domain HPD motif, driving the HSP70 chaperone cycle for
      substrate binding, folding, and release. Directly demonstrated in vitro with
      purified recombinant DNAJA2, Hsp72, and nucleotide exchange factors
      (PMID:24318877). The J-domain interaction is also critical for DNAJA2 oligomer
      regulation: an HPD-to-QPN mutation prevents productive Hsc70 engagement and
      impairs ATP-dependent oligomer disassembly, supporting the model that J-domain-
      stimulated ATPase cycling triggers release of active DNAJA2 dimers from the
      tubular storage form (DOI:10.1038/s41467-023-41150-8). ATPase stimulation is
      also required for DNAJA2-dependent degradation functions, as the J-domain
      deletion mutant (DJA2-deltaJ) fails to promote CFTR ERAD
      (DOI:10.1371/journal.pone.0220984).
    supported_by:
      - reference_id: PMID:24318877
        supporting_text: >-
          we combined the Hsp70-NEF pairs with cochaperones of the J protein family
          (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The
          activity of the combinations in ATPase and luciferase refolding assays were
          dependent on the identity and stoichiometry of both the J protein and NEF so
          that some combinations were potent chaperones, whereas others were inactive.
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
    locations:
      - id: GO:0005829
        label: cytosol
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:21231916
  title: The diverse members of the mammalian HSP70 machine show distinct chaperone-like
    activities.
  findings: []
- id: PMID:22085931
  title: Optimal functional levels of activation-induced deaminase specifically require
    the Hsp40 DnaJa1.
  findings: []
- id: PMID:24318877
  title: Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70)
    generates functionally distinct complexes in vitro.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:9383053
  title: Human CPR (cell cycle progression restoration) genes impart a Far- phenotype
    on yeast cells.
  findings: []
- id: Reactome:R-HSA-3371422
  title: ATP hydrolysis by HSP70
  findings: []
- id: Reactome:R-HSA-3371503
  title: STIP1(HOP) binds HSP90 and HSP70:HSP40:nascent protein
  findings: []
- id: Reactome:R-HSA-3371590
  title: HSP70 binds to HSP40:nascent protein
  findings: []
- id: DOI:10.1038/s41467-023-41150-8
  title: The self-association equilibrium of DNAJA2 regulates its interaction with
    unfolded substrate proteins and with Hsc70.
  findings:
    - statement: >-
        DNAJA2 reversibly self-assembles into highly ordered tubular oligomers (~200
        angstrom width, D5 symmetry disks of five dimers) that can dissociate into
        active dimers; heat shock at 40 degrees C promotes dissociation with t1/2 ~2.3
        min.
    - statement: >-
        The intrinsically disordered C-terminal tail (V361-Q412) regulates holding
        activity and productive Hsc70 interaction.
    - statement: >-
        Hsc70 drives DNAJA2 oligomer disassembly in an ATP-dependent manner via
        J-domain engagement.
- id: DOI:10.1371/journal.pone.0220984
  title: Hsp70 and DNAJA2 limit CFTR levels through degradation.
  findings:
    - statement: >-
        DNAJA2 overexpression reduces CFTR maturation, consistent with increased ERAD
        of immature CFTR, in a J-domain-dependent manner.
    - statement: >-
        DNAJA2 acts with Hsc70/Hsp70 and the E3 ubiquitin ligase CHIP to promote CFTR
        degradation at the ER.
- id: DOI:10.1038/s41467-023-40952-0
  title: DNAJA2 deficiency activates cGAS-STING pathway via the induction of
    aberrant mitosis and chromosome instability.
  findings:
    - statement: >-
        DNAJA2 localizes to centrosomes and promotes CMA-dependent degradation of PCM1
        and CEP290 via Hsc70/LAMP2A.
    - statement: >-
        Loss of DNAJA2 causes abnormal mitosis (~50% abnormal spindles), chromosome
        instability, and micronuclei formation activating cGAS-STING innate immunity.
- id: DOI:10.1038/s41421-023-00601-8
  title: Heat shock protein DNAJA2 regulates transcription-coupled repair by
    triggering CSB degradation via chaperone-mediated autophagy.
  findings:
    - statement: >-
        DNAJA2 facilitates Hsc70-dependent CMA to degrade CSB during
        transcription-coupled nucleotide excision repair.
    - statement: >-
        CSB must translocate from nucleus to cytosol for LAMP2A-dependent lysosomal
        degradation.
- id: DOI:10.7554/elife.69601
  title: Hsp40s play complementary roles in the prevention of tau amyloid formation.
  findings:
    - statement: >-
        DNAJA2 potently suppresses tau amyloid formation using at least two binding
        sites; CTDI recognizes monomeric tau while CTDII binds aggregation-prone
        species and mature fibrils.
    - statement: >-
        At sub-stoichiometric DNAJA2:tau ratios (0.5:1), 88% reduction in fibril mass
        was observed.
- id: DOI:10.1038/s41594-018-0057-1
  title: Mapping interactions with the chaperone network reveals factors that protect
    against tau aggregation.
  findings:
    - statement: >-
        Systems-level chaperone-tau interaction survey identified DNAJA2 as a potent
        tau aggregation inhibitor across ~600 combinations.
    - statement: >-
        DNAJA2 levels correlated with tau pathology in human brain samples.
- id: DOI:10.1128/mcb.01592-06
  title: Definition of pRb- and p53-dependent and -independent steps in
    HIRA/ASF1a-mediated formation of senescence-associated heterochromatin foci.
  findings:
    - statement: >-
        DNAJA2 (as HIRIP4) interacts with HIRA and pRb in the context of
        senescence-associated heterochromatin foci (SAHF) formation.
- id: DOI:10.3390/ijms222413527
  title: Regulation of p53 and cancer signaling by heat shock protein 40/J-domain
    protein family members.
  findings:
    - statement: >-
        Review of J-domain protein family including DNAJA2, emphasizing role as
        specificity determinants for Hsp70 functional outcomes including client
        triage between folding and degradation.