HSPA4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000774 adenyl-nucleotide exchange factor activity	IBA GO_REF:0000033	ACCEPT	Summary: Hsp70 nucleotide-exchange factor activity is the defining molecular activity of the Hsp110 clade and is directly demonstrated for human Apg2/HSPA4 acting on Hsc70. Reason: The PAINT node PTN002900795 was seeded with experimental nucleotide-exchange annotations of yeast SSE1 (S000006027), SSE2 (S000000373) and LHS1 (S000001556), a Candida Hsp110 and human HSPH1 (Q92598). HSPA4 sits in PANTHER subfamily PTHR45639:SF6 inside that Hsp110/Grp170 clade, so the IBA is a sound phylogenetic inference, and it is independently confirmed for HSPA4 by purified-protein work showing that Apg2 acts as a specialised nucleotide-exchange factor for human Hsc70 (HSPA8) in aggregate reactivation. Core molecular function. Supporting Evidence: PMID:30521813 Hsp110s support the refolding of aggregated polypeptides acting as specialized nucleotide exchange factors of Hsp70. PMID:36167183 During aggregate reactivation, Apg2 performs as a specialized nucleotide exchange factor file:interpro/panther/PTHR45639/PTHR45639-paint.tsv CGD:CAL0000182153\|SGD:S000000373\|SGD:S000001556\|SGD:S000006027\|UniProtKB:Q92598
GO:0005515 protein binding	IPI PMID:20029029 Regulation of epidermal growth factor receptor trafficking b...	REMOVE	Summary: EGFR membrane yeast two-hybrid interaction; bare protein binding is uninformative. Reason: This row records HSPA4 among 87 candidate partners of ligand-unoccupied EGFR found by a membrane yeast two-hybrid screen. The interaction is not claimed to be false, but bare protein binding carries no functional information and no evidence ties HSPA4 to an EGFR-directed activity, so under the repository protein-binding policy it is removed rather than replaced. Supporting Evidence: PMID:20029029 We used a modified membrane yeast two-hybrid system together with bioinformatics to identify 87 candidate proteins interacting with the ligand-unoccupied EGFR.
GO:0005515 protein binding	IPI PMID:22990239 Metazoan Hsp70 machines use Hsp110 to power protein disaggre...	MODIFY	Summary: Interaction with HSPA8 (Hsc70) is the functional NEF-substrate interaction of HSPA4; replace bare protein binding with Hsp70 protein binding. Reason: The partner is HSPA8, the Hsp70 whose nucleotide-binding domain HSPA4 engages as an exchange factor. Rampelt et al. showed that Hsp110 remodels the human Hsp70-Hsp40 system into a disaggregase through nucleotide exchange, and purified Apg2 forms a nucleotide-dependent complex with Hsc70. The interaction is therefore informative and is better captured by GO:0030544 Hsp70 protein binding; the catalytic consequence is captured separately by GO:0000774. Proposed replacements: Hsp70 protein binding Supporting Evidence: PMID:22990239 We show that instead the Hsp110 member of the Hsp70 superfamily remodels the human Hsp70-Hsp40 system to efficiently disaggregate and refold aggregates of heat and chemically denatured proteins in vitro and in cell extracts. PMID:36167183 interacts with the nucleotide binding domain of Hsc70 in a nucleotide-dependent manner, contributing significantly to the stability of the Hsc70:Apg2 complex
GO:0005515 protein binding	IPI PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing ...	REMOVE	Summary: EGFR interaction from the MaMTH membrane two-hybrid method paper; uninformative bare protein binding. Reason: A methods paper for membrane-protein two-hybrid screening recovered HSPA4 with EGFR. No functional consequence for HSPA4 is reported, so the bare protein-binding row is removed under the protein-binding policy; removal does not assert that the interaction is false.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: AGTRAP interaction from a proteome-scale binary Y2H map; uninformative. Reason: High-throughput yeast two-hybrid interaction with AGTRAP without functional follow-up. Bare protein binding is uninformative and there is no basis for a more specific HSPA4 activity toward AGTRAP, so the row is removed under the protein-binding policy.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: APPBP2 interaction from a proteome-scale binary Y2H map; uninformative. Reason: High-throughput yeast two-hybrid interaction with APPBP2 (also recovered in the later reference binary map). No functional consequence is defined for HSPA4, so bare protein binding is removed under the protein-binding policy.
GO:0005515 protein binding	IPI PMID:29568061 An AP-MS- and BioID-compatible MAC-tag enables comprehensive...	MODIFY	Summary: HSPA8 co-purification in a MAC-tag AP-MS/BioID map; the partner is the Hsp70 that HSPA4 regulates, so replace with Hsp70 protein binding. Reason: Although high-throughput, this row records the same HSPA4-HSPA8 interaction that is mechanistically characterised with purified proteins. It is made consistent with the other HSPA8 rows by replacing bare protein binding with GO:0030544 Hsp70 protein binding. Proposed replacements: Hsp70 protein binding Supporting Evidence: PMID:30521813 Our data support a mechanism in which Apg2 arrests the chaperone cycle through an interaction with Hsc70(ATP) that might lead to premature ATP dissociation before hydrolysis.
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	MODIFY	Summary: HSPA8 crosslink from nuclear crosslinking mass spectrometry; replace with Hsp70 protein binding. Reason: The partner is HSPA8. The HSPA4-Hsc70 interaction is the mechanistic basis of HSPA4 exchange activity, so this row is replaced with GO:0030544 Hsp70 protein binding, consistent with the other HSPA8 rows. Proposed replacements: Hsp70 protein binding Supporting Evidence: PMID:36167183 interacts with the nucleotide binding domain of Hsc70 in a nucleotide-dependent manner, contributing significantly to the stability of the Hsc70:Apg2 complex
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	REMOVE	Summary: EGFR co-purification in a colorectal-cancer EGFR interactome; uninformative. Reason: An AP-MS survey of the EGFR network recovered HSPA4. Abundant cytosolic chaperones are common co-purifying proteins, and no specific HSPA4 activity toward EGFR is defined, so bare protein binding is removed under the protein-binding policy.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: POU6F2 interaction from the HuRI binary map; uninformative. Reason: High-throughput yeast two-hybrid interaction with the transcription factor POU6F2 without functional follow-up; bare protein binding is removed under the protein-binding policy.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: APPBP2 interaction from the HuRI binary map; uninformative. Reason: High-throughput yeast two-hybrid interaction with APPBP2 without functional follow-up; bare protein binding is removed under the protein-binding policy.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: HSPA8 co-purification in the BioPlex dual-cell-line network; replace with Hsp70 protein binding. Reason: The partner is HSPA8, the Hsp70 whose nucleotide cycle HSPA4 regulates. Replaced with GO:0030544 Hsp70 protein binding for consistency with the mechanistically characterised interaction. Proposed replacements: Hsp70 protein binding Supporting Evidence: PMID:30521813 Our data support a mechanism in which Apg2 arrests the chaperone cycle through an interaction with Hsc70(ATP) that might lead to premature ATP dissociation before hydrolysis.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MODIFY	Summary: HSPA8 interaction in a multimodal cell-map study; replace with Hsp70 protein binding. Reason: The partner is HSPA8. Replaced with GO:0030544 Hsp70 protein binding for consistency with the mechanistically characterised Hsc70-Apg2 complex. Proposed replacements: Hsp70 protein binding Supporting Evidence: PMID:36167183 interacts with the nucleotide binding domain of Hsc70 in a nucleotide-dependent manner, contributing significantly to the stability of the Hsc70:Apg2 complex
GO:0005524 ATP binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: HSPA4 retains the Hsp70-superfamily nucleotide-binding domain; ATP binding is correct but is a mechanistic property supporting exchange activity rather than the core function. Reason: HSPA4 carries the Hsp70-family nucleotide-binding domain (InterPro IPR013126, Pfam PF00012), and Hsp110 proteins engage Hsp70 in their ATP-bound state. ATP binding is thus true, but it is a property enabling the exchange-factor activity rather than an independent function, so it is retained as non-core. Supporting Evidence: file:human/HSPA4/HSPA4-uniprot.txt DR InterPro; IPR013126; Hsp_70_fam.
GO:0005524 ATP binding	NAS PMID:8335910 Molecular cloning of a novel human hsp70 from a B cell line ...	KEEP AS NON CORE	Summary: The cloning paper notes the Hsp70-type N-terminal ATP-binding domain; consistent with the IEA row. Reason: The original cDNA cloning paper describes the characteristic Hsp70 N-terminal ATP-binding domain. This is a sequence-based statement, consistent with the domain-based IEA row, and is retained as non-core for the same reason. Supporting Evidence: PMID:8335910 has the characteristic N-terminal ATP-binding domain and the C-terminal peptide binding domain
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Nuclear localisation inherited from the eukaryotic Hsp110 node; plausible but peripheral to the cytosolic exchange function. Reason: PTN000452854 is the eukaryote-wide Hsp110 node (seeded by Arabidopsis HSP110 proteins, mouse and human HSPH1) from which HSPA4 also inherits cytosol and protein folding. HSPA4 is in that clade and there is no HSPA4-specific evidence of exclusion from the nucleus, so the inference is retained. It is not the principal site of HSPA4 action, which is the cytosol, hence non-core. Supporting Evidence: file:interpro/panther/PTHR45639/PTHR45639-paint.tsv AGI_LocusCode:AT1G79930\|MGI:MGI:105053\|UniProtKB:F4HQD4\|UniProtKB:Q92598
GO:0005737 cytoplasm	IEA GO_REF:0000044	MODIFY	Summary: Correct but general; HSPA4 is a soluble cytosolic Hsp110, and cytosol is already annotated by IDA and IBA. Reason: The UniProt cytoplasm statement is correct but less specific than the evidence, which places HSPA4 in the cytosol (cytosol IDA from overexpression studies of the mammalian HSP70 machinery and cytosol IBA from the Hsp110 node). Refine to GO:0005829 cytosol, a term HSPA4 already carries. Proposed replacements: cytosol Supporting Evidence: PMID:36167183 Apg2, one of the three cytosolic Hsp110 chaperones in humans, supports reactivation of unordered and ordered protein aggregates by Hsc70 (HspA8).
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Cytosol is the site of HSPA4 exchange-factor activity; the IBA is phylogenetically sound and includes HSPA4's own experimental annotation among its donors. Reason: The Hsp110 node PTN000452854 carries cytosol from Arabidopsis, HSPA4L, HSPH1 and HSPA4 itself (P34932, from its own cytosol IDA), which is the expected grounding for an IBA, not circularity. Apg2 is described as one of three cytosolic human Hsp110s acting on Hsc70. Supporting Evidence: PMID:36167183 Apg2, one of the three cytosolic Hsp110 chaperones in humans, supports reactivation of unordered and ordered protein aggregates by Hsc70 (HspA8).
GO:0005829 cytosol	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	Summary: Cytosolic localisation from the comparative study of overexpressed mammalian HSP70-machine members. Reason: Hageman et al. examined overexpressed human HSPA/HSPH and DNAJ members and report that most are cytosolic; the UniProt curator who read the full text assigned HSPA4 cytosol by IDA. Consistent with the biochemistry of Apg2 as a cytosolic Hsc70 exchange factor. Supporting Evidence: PMID:21231916 most of the corresponding proteins are localized in the cytosol
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: HSPA4 participates in Hsc70-dependent refolding of misfolded and aggregated proteins by performing the nucleotide-exchange step of the chaperone cycle. Reason: The IBA is inherited from the Hsp110 node seeded by yeast SSE1/SSE2, Candida Hsp110, mouse Hsph1 and worm HSP-110. For HSPA4 itself, purified Apg2 stimulates the Hsc70 ATPase cycle, aggregate binding and refolding of the system at substoichiometric concentration. HSPA4 does part of the work of the folding/refolding reaction (the exchange step), so this is participation, not mere necessity. PAINT placed the more specific protein refolding term (GO:0042026) only at the broader Hsp70 ancestral node and not at the Hsp110 node, so no more specific process is added. Supporting Evidence: PMID:30521813 Apg2 shows a biphasic behavior: at low concentration, it stimulates the ATPase cycle of Hsc70, binding of the chaperone to protein aggregates and the refolding activity of the system
GO:0006986 response to unfolded protein	NAS PMID:8335910 Molecular cloning of a novel human hsp70 from a B cell line ...	MARK AS OVER ANNOTATED	Summary: Asserted from Hsp70 sequence similarity in the cloning paper; no HSPA4-specific evidence of a stress-response role beyond its constitutive chaperone function. Reason: The 1993 cloning paper names the protein an hsp70 on sequence grounds and describes only its domain architecture and chromosomal location; it contains no stress-response experiment. HSPA4's documented role is the constitutive exchange-factor function in Hsc70-mediated folding and disaggregation, already captured by protein folding. A response-to-stimulus process for HSPA4 is not established by this reference. Supporting Evidence: PMID:8335910 has the characteristic N-terminal ATP-binding domain and the C-terminal peptide binding domain
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Generic InterPro2GO mapping from the Hsp70 family; Hsp110 function relies on nucleotide exchange, not ATP hydrolysis, and PAINT did not propagate ATP hydrolysis to the Hsp110 clade. Reason: The IPR013126 mapping applies the ATPase activity of canonical Hsp70s to every family member. In PTHR45639, PAINT curators placed GO:0016887 at the canonical Hsp70 node (PTN000452648) but not at the Hsp110 node from which HSPA4 inherits its other IBAs, which is a deliberate decision. Experimentally, the Hsp110 effect on the human Hsp70 machine relies on nucleotide exchange, not on its own ATPase activity, and the Apg2 studies measure stimulation of the Hsc70 ATPase rather than HSPA4-catalysed hydrolysis. Some Hsp110s show weak intrinsic ATPase activity, so the term is not demonstrably false, but it overstates HSPA4 function. Supporting Evidence: PMID:22990239 This Hsp110 effect relies on nucleotide exchange, not on ATPase activity, implying ATP-driven chaperoning is not required. file:interpro/panther/PTHR45639/PTHR45639-paint.tsv PTN000452648 GO:0016887
GO:0030150 protein import into mitochondrial matrix	IDA PMID:15644312 Dissection of the mitochondrial import and assembly pathway ...	UNDECIDED	Summary: Experimental annotation from a study of human Tom40 import; the HSPA4-specific experiment is not visible in the cached abstract and the full text could not be retrieved. Reason: The cached abstract describes the import and assembly of the outer-membrane channel Tom40 and implicates Hsp90 in precursor delivery; it does not mention HSPA4. The curator presumably saw an HSPA4-related result in the full text (not retrievable here), so the annotation is not rejected. Note, however, that Tom40 is an outer-membrane protein, so even if HSPA4 assists Tom40 precursor delivery, GO:0045040 protein insertion into mitochondrial outer membrane would describe the substrate's pathway better than matrix import. A cytosolic chaperone that keeps a precursor import-competent would in any case be at most upstream of the import process. Supporting Evidence: PMID:15644312 We identify that Hsp90 is involved in delivery of the Tom40 precursor to mitochondria in an ATP-dependent manner.
GO:0043226 organelle	IEA GO_REF:0000117	MODIFY	Summary: Uninformative ARBA location; the only organelle with support for HSPA4 is the nucleus, already annotated more specifically. Reason: An ARBA machine-learning rule assigns the generic term organelle. HSPA4 is chiefly cytosolic (cytosol is not an organelle); the only organelle with phylogenetic support is the nucleus, which is annotated by IBA. The general term is refined to that more specific location. Proposed replacements: nucleus Supporting Evidence: file:interpro/panther/PTHR45639/PTHR45639-paint.tsv AGI_LocusCode:AT1G79930\|MGI:MGI:105053\|UniProtKB:F4HQD4\|UniProtKB:Q92598
GO:0051131 chaperone-mediated protein complex assembly	IDA PMID:15644312 Dissection of the mitochondrial import and assembly pathway ...	UNDECIDED	Summary: Experimental annotation from the Tom40 import/assembly study; the HSPA4-specific result cannot be inspected. Reason: Tom40 assembly into the TOM complex is the subject of this paper, but the cached abstract attributes precursor delivery to Hsp90 and assembly to the TOM/SAM machinery and does not mention HSPA4. Because the curator read the full text and it could not be retrieved, the annotation is neither accepted nor rejected. Whether HSPA4 acts in Tom40 complex assembly, as opposed to keeping the precursor soluble, needs the full-text experiment. Supporting Evidence: PMID:15644312 The precursor then forms its first stable intermediate with the outer face of the TOM complex before its membrane integration and assembly.
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: Detected in the B-cell exosome proteome; a real observation but peripheral to function. Reason: HSPA4 was among 539 proteins identified by mass spectrometry of purified B-cell exosomes. Abundant cytosolic chaperones are routinely captured in extracellular vesicles; the location is retained as non-core because no exosome-specific HSPA4 function is known. Supporting Evidence: PMID:20458337 identified 539 proteins, including known and not previously identified constituents
GO:0070062 extracellular exosome	IDA PMID:21276792 Morphologic and proteomic characterization of exosomes relea...	KEEP AS NON CORE	Summary: Detected in trophoblast exosome proteome; peripheral location. Reason: Proteomic characterisation of trophoblast-derived exosomes; consistent with the HDA row, and retained as non-core for the same reason. Supporting Evidence: PMID:21276792 Ion Trap mass spectrometry demonstrated the presence of exosome marker proteins

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