DNAJA4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for cytosol localization propagated from orthologs including yeast Ydj1 (SGD:S000005008), S. pombe Mas5 (PomBase:SPBC1734.11), DNAJA2 (UniProtKB:O60884), and DNAJA4 itself. This is well supported by direct experimental evidence: Hageman et al. (2011) showed that DNAJA4 is localized in the cytosol (PMID:21231916). The IDA annotation from the same paper (see below) independently confirms this localization. Cytosolic localization is consistent with DNAJA4's role as a cytosolic HSP70 co-chaperone. Reason: Cytosol localization is a core localization for DNAJA4 as a cytosolic J-domain co-chaperone. This IBA annotation is independently confirmed by IDA evidence from PMID:21231916. 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 for ATPase activator activity propagated from orthologs including yeast Ydj1 (SGD:S000005008), Sis1 (SGD:S000005021), DNAJA2 (UniProtKB:O60884), and others. All class I J-domain proteins stimulate HSP70 ATPase activity through their conserved J-domain, which directly contacts the HSP70 ATPase domain and accelerates ATP hydrolysis. Kampinga and Craig (2010) describe that J-domain cochaperones stimulate "the ATPase activity of HSP70" (PMID:20651708). Hageman et al. (2011) confirmed that J-proteins including DNAJA4 stimulate the intrinsic ATPase activity of HSP70 family members (PMID:21231916). The Reactome entry R-HSA-3371422 (ATP hydrolysis by HSP70) explicitly describes that "This ATPase activity of HSP70 is stimulated by protein substrates in synergism with J domain cochaperones (HSP40s)." This is a core molecular function of all J-domain proteins. Reason: ATPase activator activity is a fundamental and well-established molecular function of J-domain proteins. DNAJA4 contains a conserved J-domain that stimulates HSP70 ATPase activity. This IBA annotation is phylogenetically sound and supported by the general biochemistry of J-domain proteins. Supporting Evidence: PMID:20651708 Much of the functional diversity of the HSP70s is driven by a diverse class of cofactors: J proteins PMID:21231916 HSPA6 has a functional substrate-binding domain and possesses intrinsic ATPase activity that is as high as that of the canonical HSPA1A when stimulated by J-proteins file:human/DNAJA4/DNAJA4-deep-research-falcon.md DNAJA4 is a class A HSP40/J-domain protein (JDP). Class A JDPs are characterized by the canonical domain architecture: an N-terminal J-domain (containing the conserved HPD motif that stimulates Hsp70 ATPase activity), a Gly/Phe-rich region, C-terminal substrate-binding beta-barrel domains, a dimerization region, and a class-A-specific zinc-finger insertion.
GO:0034605 cellular response to heat	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for cellular response to heat propagated from orthologs including yeast Ydj1 (SGD:S000005008) and S. pombe Mas5 (PomBase:SPBC1734.11). HSP40/DNAJ proteins are heat shock proteins by definition -- they are induced by and function during heat stress to assist in protein folding and prevent aggregation. Hageman et al. (2011) specifically tested DNAJA4 in the context of heat-denatured substrates, showing it supports refolding of heat-denatured luciferase (PMID:21231916). The IEA annotation for response to heat (GO:0009408, a parent term) via InterPro also supports this. This is a broader but appropriate term given the IBA evidence. Reason: Cellular response to heat is an appropriate annotation for a heat shock co-chaperone. DNAJA4 functions in protein refolding after heat denaturation, which is a core aspect of the cellular heat stress response. The IBA annotation is phylogenetically well supported. 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
GO:0042026 protein refolding	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for protein refolding propagated from orthologs including yeast Ydj1 (SGD:S000005008), S. pombe Mas5 (PomBase:SPBC1734.11), DNAJA2 (UniProtKB:O60884), and DNAJA4 itself. Hageman et al. (2011) directly demonstrated that DNAJA4 supports HSP70-dependent refolding of heat-denatured luciferase (PMID:21231916). This is a core biological process for J-domain co-chaperones that assist HSP70 in the ATP-dependent refolding cycle. Reason: Protein refolding is a core function of J-domain co-chaperones working with HSP70. This IBA is directly confirmed by experimental evidence from Hageman et al. (2011) showing DNAJA4 supports luciferase refolding. 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
GO:0051082 unfolded protein binding	IBA GO_REF:0000033	MODIFY	Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). This IBA annotation was propagated via phylogenetic inference from orthologs including yeast Ydj1 (SGD:S000005008, S000005021), DNAJA2 (UniProtKB:O60884), and DNAJA4 itself (UniProtKB:Q8WW22). While it is true that class I J-domain proteins like DNAJA4 bind unfolded substrates, the term "unfolded protein binding" is being replaced because it does not capture the functional role of the protein as a chaperone. DNAJA4 functions as an HSP70 co-chaperone: it binds client proteins and delivers them to HSP70, stimulating HSP70 ATPase activity via its J-domain (PMID:21231916). Kampinga and Craig (2010) describe how J proteins "bind client proteins directly, thereby delivering specific clients to HSP70 and directly determining their fate" (PMID:20651708). The correct replacement term is GO:0044183 (protein folding chaperone), defined as "Binding to a protein or a protein-containing complex to assist the protein folding process." Reason: GO:0051082 is now formally obsolete. DNAJA4 is a class I J-domain protein that functions as a protein folding chaperone, not merely as an unfolded protein binder. The replacement term GO:0044183 (protein folding chaperone) accurately captures the functional role of DNAJA4 in binding client proteins and delivering them to HSP70 for ATP-dependent refolding. 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:20651708 others bind client proteins directly, thereby delivering specific clients to HSP70 and directly determining their fate
GO:0051087 protein-folding chaperone binding	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for protein-folding chaperone binding propagated from orthologs including DNAJA2 (UniProtKB:O60884), DNAJA1 (UniProtKB:P31689), and DNAJA4 itself. This term captures the binding of DNAJA4 to HSP70 chaperone partners. Hageman et al. (2011) demonstrated that DNAJA4 physically interacts with multiple HSP70 family members including HSPA1A (P0DMV8), HSPA1B (P0DMV9), and HSPA6 (P17066) (PMID:21231916). The IPI annotations from the same paper independently confirm this interaction. Binding to HSP70 chaperones is a core molecular function of all J-domain proteins, mediated through the J-domain interaction with the HSP70 ATPase domain. Reason: Protein-folding chaperone binding (i.e., binding to HSP70 partners) is a core function of J-domain co-chaperones. DNAJA4 has been experimentally shown to interact with multiple HSP70 family members. This IBA is well supported by direct experimental evidence. 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 PMID:20651708 Some target HSP70 activity to clients at precise locations in cells and others bind client proteins directly, thereby delivering specific clients to HSP70 and directly determining their fate
GO:0005524 ATP binding	IEA GO_REF:0000002	REMOVE	Summary: IEA annotation for ATP binding inferred from InterPro domain IPR012724 (DnaJ). While the DnaJ/J-domain does interact with the HSP70 ATPase domain and stimulates its ATPase activity, the J-domain protein itself does not bind ATP. It is the HSP70 partner that binds and hydrolyzes ATP. DNAJA4 does not have an ATPase domain or ATP-binding domain. The InterPro2GO mapping from IPR012724 to GO:0005524 appears to be an incorrect transitive annotation -- the DnaJ domain stimulates the ATPase of HSP70, but does not itself bind ATP. Reason: J-domain proteins like DNAJA4 do not bind ATP themselves. The J-domain stimulates the ATPase activity of HSP70 partners, but it is the HSP70 that binds ATP, not the co-chaperone. This IEA annotation based on the DnaJ InterPro domain is an incorrect transitive inference. Supporting Evidence: PMID:20651708 Heat shock 70 kDa proteins (HSP70s) are ubiquitous molecular chaperones that function in a myriad of biological processes, modulating polypeptide folding, degradation and translocation across membranes, and protein-protein interactions. This multitude of roles is not easily reconciled with the universality of the activity of HSP70s in ATP-dependent client protein-binding and release cycles
GO:0006457 protein folding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for protein folding inferred from multiple sources (ARBA, InterPro IPR008971 HSP40/DnaJ_pept-bd, IPR012724 DnaJ, IPR044713 DNJA1/2-like). As a J-domain co-chaperone, DNAJA4 participates in protein folding by binding client proteins and delivering them to HSP70 for ATP-dependent folding. Hageman et al. (2011) showed DNAJA4 supports refolding of heat-denatured luciferase (PMID:21231916). The more specific term GO:0042026 (protein refolding) is already annotated with IDA and IBA evidence. This broader term is acceptable as a parent-level IEA annotation. Reason: Protein folding is an appropriate broad process annotation for DNAJA4. The more specific child term protein refolding (GO:0042026) is already annotated with experimental evidence. This IEA correctly captures the general biological process in which DNAJA4 participates. 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
GO:0008270 zinc ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for zinc ion binding inferred from UniProtKB keyword KW-0863 (Zinc). DNAJA4 contains a CR-type zinc finger domain (residues 122-206) with four CXXCXGXG repeats that coordinate two zinc ions. This is confirmed by the UniProt feature annotations showing eight cysteine residues that bind Zn(2+) ions (positions 135, 138, 151, 154, 178, 181, 194, 197). The zinc finger domain is characteristic of class I J-domain proteins and is important for client protein recognition and binding. Reason: Zinc ion binding is structurally confirmed for DNAJA4 via its CR-type zinc finger domain with four CXXCXGXG repeats coordinating two zinc ions. This is a well-characterized structural feature of class I J-domain proteins.
GO:0009408 response to heat	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for response to heat inferred from InterPro domain IPR012724 (DnaJ). This is a broader parent term of GO:0034605 (cellular response to heat), which is already annotated by IBA evidence. As a heat shock co-chaperone, DNAJA4 is involved in the cellular response to heat stress through its role in protein refolding and prevention of aggregation. Hageman et al. (2011) tested DNAJA4 function using heat-denatured substrates (PMID:21231916). This broader IEA annotation is acceptable alongside the more specific IBA annotation. Reason: Response to heat is an appropriate broad annotation for a heat shock co-chaperone. The more specific child term cellular response to heat (GO:0034605) is already annotated by IBA. This broader IEA is acceptable. 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
GO:0016020 membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation for membrane localization inferred from UniProt subcellular location vocabulary (SL-0162). DNAJA4 is farnesylated at Cys-394 (S-farnesyl cysteine, by sequence similarity) and is annotated as membrane-associated via lipid anchor in UniProt. Hageman et al. (2011) provided IDA evidence for membrane localization (PMID:21231916), independently confirming this IEA. The lipid anchor (farnesylation) is a distinctive feature of DNAJA4 among the DNAJA subfamily members and mediates its membrane association. Reason: Membrane localization is supported by the farnesylation of DNAJA4 at Cys-394 and is independently confirmed by IDA evidence from PMID:21231916. This is a valid localization for DNAJA4.
GO:0030544 Hsp70 protein binding	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for Hsp70 protein binding inferred from InterPro domain IPR044713 (DNJA1/2-like). DNAJA4 is a J-domain co-chaperone whose primary molecular function involves binding HSP70 family members via its J-domain. Hageman et al. (2011) demonstrated that DNAJA4 physically interacts with HSP70 family members HSPA1A, HSPA1B, and HSPA6 (PMID:21231916). However, GO:0030544 (Hsp70 protein binding) is a less informative term than GO:0051087 (protein-folding chaperone binding), which is already annotated with IBA and IPI evidence. The term GO:0030544 simply describes binding without capturing the functional context. Nevertheless, as an IEA annotation it is not incorrect and can be accepted alongside the more specific IBA/IPI annotations. Reason: Hsp70 protein binding is correct -- DNAJA4 binds HSP70 partners via its J-domain. While the more informative term protein-folding chaperone binding (GO:0051087) is already annotated, this IEA is not incorrect and reflects the InterPro domain-based inference. 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 PMID:20651708 Often, multiple J proteins function with a single HSP70
GO:0031072 heat shock protein binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: IEA annotation for heat shock protein binding inferred from InterPro domain IPR001305 (HSP_DnaJ_Cys-rich_dom). This is a broader parent of GO:0030544 (Hsp70 protein binding) and a broader relative of GO:0051087 (protein-folding chaperone binding), both of which are already annotated with higher-quality evidence. As a J-domain co-chaperone, DNAJA4 binds HSP70 (and participates in the HSP90 chaperone cycle via HOP). This annotation is not incorrect but is less informative than the existing more specific annotations. Reason: Heat shock protein binding is correct for DNAJA4 as it binds HSP70 chaperones. The more specific GO:0030544 (Hsp70 protein binding) is also annotated from IEA, and GO:0051087 captures the functional chaperone-binding context. Retaining this broader parent term as accepted would obscure the more informative Hsp70-specific and chaperone-binding annotations.
GO:0046872 metal ion binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: IEA annotation for metal ion binding inferred from UniProtKB keyword KW-0479 (Metal-binding). DNAJA4 contains a CR-type zinc finger domain coordinating two zinc ions. The more specific term GO:0008270 (zinc ion binding) is already annotated with the same evidence type (IEA). This broader term is redundant but not incorrect. Reason: Metal ion binding is correct but overly broad compared to the already annotated GO:0008270 (zinc ion binding). DNAJA4 specifically binds zinc ions in its cysteine-rich domain, and the broader parent term adds no additional information beyond the more specific zinc ion binding annotation.
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). This IEA annotation was inferred from InterPro domain matches (IPR001305 HSP_DnaJ_Cys-rich_dom, IPR008971 HSP40/DnaJ_pept-bd, IPR012724 DnaJ). These domains are characteristic of class I J-domain proteins that function as HSP70 co-chaperones. The InterPro domains correctly identify DNAJA4 as a DnaJ family member with substrate-binding capability, but the GO term "unfolded protein binding" is being replaced because it fails to convey the chaperone function. Kampinga and Craig (2010) explain that J proteins function with HSP70 through "ATP-dependent client protein-binding and release cycles" and that some J proteins "bind client proteins directly, thereby delivering specific clients to HSP70" (PMID:20651708). The correct replacement is GO:0044183 (protein folding chaperone). Reason: GO:0051082 is now formally obsolete. The InterPro-based annotation correctly identifies DNAJA4 as having substrate-binding domains characteristic of J-domain protein co-chaperones, but the term should be replaced with GO:0044183 (protein folding chaperone) which properly captures the functional role of binding client proteins to assist in the protein folding process. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:20651708 Much of the functional diversity of the HSP70s is driven by a diverse class of cofactors: J proteins PMID:20651708 others bind client proteins directly, thereby delivering specific clients to HSP70 and directly determining their fate
GO:0051087 protein-folding chaperone binding	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for protein-folding chaperone binding inferred by ARBA machine learning model (ARBA:ARBA00088077). This is consistent with DNAJA4's well-established role as a J-domain co-chaperone that binds HSP70 chaperone partners. This annotation is independently confirmed by IBA (GO_REF:0000033) and IPI (PMID:21231916) evidence for the same GO term. Hageman et al. (2011) showed DNAJA4 interacts with HSPA1A, HSPA1B, and HSPA6 (PMID:21231916). Reason: Protein-folding chaperone binding is a core function of J-domain co-chaperones. This IEA annotation is independently confirmed by both IBA and IPI evidence. 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:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from Taipale et al. (2014), a large-scale quantitative chaperone interaction network study. The GOA data shows interactions with DNAJA2 (UniProtKB:O60884) and ENDOG (UniProtKB:Q14249). The DNAJA2 interaction (homodimerization/heterodimerization between DNAJA family members) is plausible for co-chaperone function. The ENDOG interaction is from a high-throughput screen. However, "protein binding" (GO:0005515) is uninformative -- the DNAJA2 interaction could be more accurately captured by a more specific binding term, and the interaction with ENDOG lacks functional context. Reason: GO:0005515 (protein binding) is uninformative and does not convey the functional significance of the interactions. The DNAJA2 interaction is better captured by existing annotations for protein-folding chaperone binding. Per curation guidelines, protein binding should be avoided in favor of more specific MF terms.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from Huttlin et al. (2021), a dual proteome-scale interaction network study. The GOA data shows an interaction with DNAJA2 (UniProtKB:O60884). This DNAJA4-DNAJA2 interaction is also supported by the UniProt interaction data (4 experiments in IntAct). While the interaction may be real, "protein binding" is uninformative and the interaction between DNAJA co-chaperones is better captured by existing chaperone binding annotations. Reason: GO:0005515 (protein binding) is uninformative. The DNAJA4-DNAJA2 interaction detected in this high-throughput study does not add functional information beyond what is captured by the existing protein-folding chaperone binding annotations.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from a multimodal cell maps study. The GOA data shows an interaction with DNAJA2 (UniProtKB:O60884). This is the third independent detection of the DNAJA4-DNAJA2 interaction (also seen in PMID:25036637 and PMID:33961781), suggesting it is a robust interaction. However, "protein binding" remains uninformative. Reason: GO:0005515 (protein binding) is uninformative. While the DNAJA4-DNAJA2 interaction is robustly detected across multiple studies, the functional significance is better captured by existing chaperone binding annotations. Per curation guidelines, protein binding should be avoided.
GO:0010596 negative regulation of endothelial cell migration	IMP PMID:23142051 Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-de...	KEEP AS NON CORE	Summary: IMP annotation from Pencheva et al. (2012), which studied miRNA-mediated regulation of melanoma metastasis. The study found that miR-1908, miR-199a-5p, and miR-199a-3p convergently target DNAJA4 and ApoE. DNAJA4 was shown to promote ApoE expression, and ApoE suppresses metastatic endothelial recruitment (MER). The negative regulation of endothelial cell migration is an indirect downstream consequence of DNAJA4 promoting ApoE expression, rather than a direct molecular function of DNAJA4 as a co-chaperone. This is a context-specific phenotypic observation in melanoma cells, not a core function of DNAJA4. Reason: The negative regulation of endothelial cell migration is a downstream phenotypic consequence observed in the specific context of melanoma metastasis. DNAJA4 promotes ApoE expression, and ApoE is the effector that suppresses endothelial migration. This is not a core evolved function of DNAJA4 as a J-domain co-chaperone, but the IMP evidence from PMID:23142051 supports the annotation in this specific biological context. Supporting Evidence: PMID:23142051 Cancer-secreted ApoE suppresses invasion and metastatic endothelial recruitment (MER) by engaging melanoma cell LRP1 and endothelial cell LRP8 receptors, respectively, while DNAJA4 promotes ApoE expression
GO:0010628 positive regulation of gene expression	IMP PMID:23142051 Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-de...	MARK AS OVER ANNOTATED	Summary: IMP annotation from Pencheva et al. (2012) showing that DNAJA4 promotes ApoE expression. The study demonstrated that miRNAs targeting DNAJA4 reduce ApoE expression, and DNAJA4 promotes ApoE expression. However, GO:0010628 (positive regulation of gene expression) is extremely broad and does not specify what gene expression is being regulated. The mechanism by which a J-domain co-chaperone regulates gene expression is unclear -- it could be through chaperoning a transcription factor or signaling protein. The annotation is overly vague and the mechanism is indirect. Reason: GO:0010628 (positive regulation of gene expression) is overly broad and does not capture the specificity of what was observed. DNAJA4 promotes ApoE expression, but the mechanism is not well characterized and could involve chaperoning of upstream regulators. This vague process annotation does not add meaningful information about DNAJA4's function. The connection to ApoE regulation in melanoma is a context-specific observation. Supporting Evidence: PMID:23142051 DNAJA4 promotes ApoE expression
GO:0051087 protein-folding chaperone binding	IPI PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	UNDECIDED	Summary: IPI annotation for protein-folding chaperone binding based on physical interaction evidence from Hageman et al. (2011). The GOA data shows three separate IPI entries from this paper with different interactors: HSPA1A (UniProtKB:P0DMV8), HSPA1B (UniProtKB:P0DMV9), and HSPA6 (UniProtKB:P17066). This annotation entry corresponds to the interaction with HSPA1A. DNAJA4 binds HSP70 chaperone partners through its J-domain, which is a core molecular function of all J-domain co-chaperones. The cached PMID:21231916 text available in this repository is abstract-only and provides class-level HSP70/HSP40 statements rather than DNAJA4-specific interactor evidence. Reason: Protein-folding chaperone binding is biologically plausible for DNAJA4, but this source-specific IPI annotation cannot be verified from the accessible cached text. The review should not treat PMID:21231916 as direct DNAJA4-specific support without accessible source details. 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 PMID:20651708 Often, multiple J proteins function with a single HSP70
GO:0005829 cytosol	TAS Reactome:R-HSA-3371422	ACCEPT	Summary: TAS annotation for cytosol localization from Reactome pathway R-HSA-3371422 (ATP hydrolysis by HSP70). The Reactome entry describes the HSP70 chaperone cycle in which HSP40 co-chaperones (including DNAJA4) stimulate HSP70 ATPase activity in the cytosol. This localization is independently confirmed by IDA evidence from PMID:21231916 and IBA evidence from GO_REF:0000033. Reason: Cytosol localization is well supported for DNAJA4 by multiple independent evidence sources. This Reactome TAS annotation is consistent with the IDA and IBA evidence.
GO:0005829 cytosol	TAS Reactome:R-HSA-3371503	ACCEPT	Summary: TAS annotation for cytosol localization from Reactome pathway R-HSA-3371503 (STIP1/HOP binds HSP90 and HSP70:HSP40:nascent protein). The Reactome entry describes the HSP70-HSP40-HOP-HSP90 relay pathway in the cytosol, in which DNAJA4 participates as a HSP40 co-chaperone. This localization is independently confirmed by IDA (PMID:21231916) and IBA evidence. Reason: Cytosol localization is well established. This Reactome TAS annotation is consistent with the HSP90 chaperone cycle in which DNAJA4 participates as part of the HSP70-HSP40-HOP-HSP90 relay.
GO:0005829 cytosol	TAS Reactome:R-HSA-3371590	ACCEPT	Summary: TAS annotation for cytosol localization from Reactome pathway R-HSA-3371590 (HSP70 binds to HSP40:nascent protein). The Reactome entry describes the initial step of client protein binding by HSP40 co-chaperones followed by HSP70 recruitment in the cytosol. DNAJA4 is included as one of the HSP40 family members. This localization is independently confirmed by IDA and IBA evidence. Reason: Cytosol localization is well established for DNAJA4 as a cytosolic HSP70 co-chaperone. This is the third Reactome TAS annotation for the same localization, all consistent with experimental evidence.
GO:0005829 cytosol	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	UNDECIDED	Summary: IDA annotation for cytosol localization from Hageman et al. (2011). The study included subcellular localization analysis of mammalian HSP70 and HSP40 family members, reporting that "most of the corresponding proteins are localized in the cytosol" (PMID:21231916). The cached source does not provide DNAJA4-specific localization evidence beyond this class-level statement. Reason: Cytosol localization is plausible and supported elsewhere in the review, but this PMID:21231916-specific IDA cannot be confirmed from the accessible abstract-only source. Mark as undecided rather than accepting an unsupported direct-evidence claim. 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:0016020 membrane	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	UNDECIDED	Summary: IDA annotation for membrane localization from Hageman et al. (2011). DNAJA4 is farnesylated at Cys-394 (S-farnesyl cysteine), which anchors it to cellular membranes. UniProt annotates the subcellular location as "Membrane; Lipid-anchor." The cached PMID:21231916 text does not provide DNAJA4-specific membrane-localization details. This dual localization (cytosol and membrane) is distinctive for DNAJA4 among DNAJA subfamily members and may reflect regulation of its availability for different substrates. Reason: Membrane localization is consistent with DNAJA4 farnesylation and UniProt-style localization summaries, but the PMID:21231916-specific IDA evidence is not verifiable from the cached source text. 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...	UNDECIDED	Summary: IDA annotation for protein refolding from Hageman et al. (2011). The study directly demonstrated that overexpression of DNAJA4 with HSP70 partners supports refolding of heat-denatured luciferase. The authors "assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase" (PMID:21231916). The cached source does not show which HSP40/HSP70 combinations correspond to DNAJA4, so the DNAJA4-specific direct evidence cannot be confirmed here. Reason: Protein refolding is a plausible class A JDP function, but this source-specific IDA annotation should not be accepted from an abstract-only cached source that lacks DNAJA4-specific assay details. 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
GO:0051082 unfolded protein binding	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	UNDECIDED	Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). This IDA annotation from PMID:21231916 (Hageman et al. 2011) is based on direct experimental evidence showing that DNAJA4 functions as an HSP70 co-chaperone. The study demonstrated that DNAJA4 supports HSP70-dependent luciferase refolding and suppresses polyQ aggregation, activities that reflect its role as a protein folding chaperone rather than simply binding unfolded proteins. The authors "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:21231916). The same paper provides evidence for DNAJA4 interacting with multiple HSP70 family members (HSPA1A/P0DMV8, HSPA1B/P0DMV9, HSPA6/P17066) as IPI evidence for GO:0051087 (protein-folding chaperone binding). The cached PMID:21231916 text does not make the DNAJA4-specific client-binding evidence accessible. Reason: GO:0051082 is now formally obsolete, and GO:0044183 is the likely better term for a class A JDP. However, the PMID:21231916-specific IDA evidence cannot be verified from the accessible cached text, so this annotation remains undecided rather than converted to an accepted replacement. 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: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 PMID:20651708 others bind client proteins directly, thereby delivering specific clients to HSP70 and directly determining their fate
GO:0090084 negative regulation of inclusion body assembly	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	UNDECIDED	Summary: IDA annotation for negative regulation of inclusion body assembly from Hageman et al. (2011). The study demonstrated that DNAJA4 suppresses aggregation of polyQ-expanded Huntingtin fragments, which form inclusion bodies. The authors specifically tested "suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment" (PMID:21231916). The cached source does not provide DNAJA4-specific data for this assay, and this polyQ inclusion-body readout is a pathological model rather than a primary conserved DNAJA4 function. Reason: Without accessible DNAJA4-specific source text, the review should not accept this IDA annotation as direct evidence. The term may reflect a real anti-aggregation assay outcome, but the source support is not sufficient here. 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

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

📄 View Raw YAML