DNAJA2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:21231916 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.
GO:0001671 ATPase activator activity	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:24318877 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. file:human/DNAJA2/DNAJA2-deep-research-falcon.md DNAJA2 is an Hsp40/J-domain protein (JDP) that acts as a co-chaperone for Hsp70-family chaperones (including the constitutively expressed Hsc70/HSPA8), stimulating Hsp70 ATPase activity via the J-domain and contributing client specificity by binding particular unfolded/misfolded client proteins.
GO:0034605 cellular response to heat	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:21231916 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.
GO:0042026 protein refolding	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:21231916 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. PMID:24318877 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.
GO:0051082 unfolded protein binding	IBA GO_REF:0000033	MODIFY	Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (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. Reason: GO:0051082 is now formally obsolete 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 replacements: protein folding chaperone Supporting Evidence: PMID:21231916 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. PMID:24318877 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.
GO:0051087 protein-folding chaperone binding	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:21231916 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.
GO:0001671 ATPase activator activity	IEA GO_REF:0000117	ACCEPT	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. 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.
GO:0005524 ATP binding	IEA GO_REF:0000002	REMOVE	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. 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.
GO:0006457 protein folding	IEA GO_REF:0000120	ACCEPT	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. 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.
GO:0008270 zinc ion binding	IEA GO_REF:0000043	ACCEPT	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. 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.
GO:0009408 response to heat	IEA GO_REF:0000002	ACCEPT	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. 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.
GO:0016020 membrane	IEA GO_REF:0000044	ACCEPT	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. 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.
GO:0030544 Hsp70 protein binding	IEA GO_REF:0000002	ACCEPT	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. 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.
GO:0031072 heat shock protein binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	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. 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. Retaining the broader parent term as a core accepted annotation would obscure the more informative Hsp70-specific binding annotation.
GO:0046872 metal ion binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	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. Reason: Metal ion binding is technically correct but overly broad. DNAJA2 specifically binds zinc ions in its cysteine-rich domain, which is captured by GO:0008270 (zinc ion binding). The broader parent term adds no additional information and should not be treated as an accepted core molecular annotation.
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	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 now formally obsolete 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). Reason: GO:0051082 is now formally obsolete 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 replacements: protein folding chaperone
GO:0051087 protein-folding chaperone binding	IEA GO_REF:0000117	ACCEPT	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. 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.
GO:0005515 protein binding	IPI PMID:22085931 Optimal functional levels of activation-induced deaminase sp...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:22085931 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.
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:25036637 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.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:32296183 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.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	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. 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). Supporting Evidence: PMID:33961781 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.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:40205054 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.
GO:0051087 protein-folding chaperone binding	IPI PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	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. 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. Supporting Evidence: PMID:21231916 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.
GO:0001671 ATPase activator activity	IDA PMID:24318877 Binding of human nucleotide exchange factors to heat shock p...	ACCEPT	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. 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. Supporting Evidence: PMID:24318877 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.
GO:0005829 cytosol	TAS Reactome:R-HSA-3371422	ACCEPT	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. 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.
GO:0005829 cytosol	TAS Reactome:R-HSA-3371503	ACCEPT	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. 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.
GO:0005829 cytosol	TAS Reactome:R-HSA-3371590	ACCEPT	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. 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.
GO:0005829 cytosol	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	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. 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. Supporting Evidence: PMID:21231916 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.
GO:0042026 protein refolding	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	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. 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. Supporting Evidence: PMID:21231916 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. PMID:24318877 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.
GO:0051082 unfolded protein binding	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	MODIFY	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 now formally obsolete 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). Reason: GO:0051082 is now formally obsolete 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 replacements: protein folding chaperone Supporting Evidence: PMID:21231916 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. PMID:24318877 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.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:19056867 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
GO:0008284 positive regulation of cell population proliferation	TAS PMID:9383053 Human CPR (cell cycle progression restoration) genes impart ...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:9383053 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.

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