HSPH1 (Hsp105/Hsp110) is a member of the Hsp110 family, a significantly diverged subgroup of the Hsp70 superfamily. It has two core molecular functions: (1) holdase chaperone activity, preventing the aggregation of heat-denatured proteins by maintaining them in a soluble, folding-competent state (significantly more efficient than Hsc70 at this function), and (2) nucleotide exchange factor (NEF) activity for Hsp70 family members (HSPA1A, HSPA1B), promoting ADP release and triggering substrate release. Importantly, HSPH1 does NOT itself refold denatured proteins; refolding requires Hsc70/Hdj-1. HSPH1 also inhibits HSPA8/HSC70 ATPase activity. Overexpression confers substantial thermoresistance in vivo.
Definition: Binding of unfolded or misfolded proteins to prevent their aggregation, without actively catalyzing refolding. This activity maintains client proteins in a soluble, folding-competent state for subsequent refolding by other chaperone systems.
Justification: Multiple proteins including HSPH1/Hsp110, small HSPs (CRYAA, CRYAB, HSPB6), and clusterin (CLU) function as holdases rather than foldases. The current GO term GO:0044183 (protein folding chaperone) implies active folding, which does not accurately describe holdase function. See go-ontology#30552.
Parent term: protein folding chaperone
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IEA GO_REF:0000118 | KEEP AS NON CORE | Summary: TreeGrafter-inferred nuclear localization. UniProt subcellular location for Q60446 lists only cytoplasm (by similarity to human Q92598). However, the deep research review (HSPH1-deep-research-falcon.md) notes that Hsp105alpha (HSPH1) localizes constitutively to both cytoplasm and nucleus in multiple mammalian tissues, including brain. The TreeGrafter inference is therefore supported by recent literature on mammalian orthologs. Reason: Nuclear localization is supported by literature on mammalian HSPH1 orthologs. The deep research review cites Chuang et al. 2024 as reporting constitutive cytoplasmic and nuclear localization. However, the primary functional compartment is the cytosol where the holdase and NEF activities operate. Keeping as non-core since it is a secondary localization. Supporting Evidence: file:CRIGR/HSPH1/HSPH1-deep-research-falcon.md Constitutive cytoplasmic and nuclear localization is reported for Hsp105alpha (HSPH1) [in mammalian tissues] |
| GO:0005829 cytosol | IEA GO_REF:0000118 | ACCEPT | Summary: TreeGrafter-inferred cytosol localization, consistent with UniProt annotation of cytoplasm for HSPH1 (by similarity to human Q92598). HSPH1 is a cytoplasmic chaperone and its holdase and NEF functions operate in the cytoplasm. The deep research review (HSPH1-deep-research-falcon.md) confirms cytosolic localization as the primary site of HSPH1 function. Reason: Cytosol is the primary localization for HSPH1, consistent with UniProt annotation of cytoplasm and with its known functions as a cytoplasmic chaperone and NEF. Supporting Evidence: PMID:9395504 hsp110 is one of the principal molecular chaperones of mammalian cells |
| GO:0006457 protein folding | IEA GO_REF:0000118 | KEEP AS NON CORE | Summary: TreeGrafter-inferred involvement in protein folding. HSPH1 is involved in protein folding homeostasis, but importantly it is a holdase, not a foldase. It maintains denatured proteins in a folding-competent state but does NOT actively refold them (PMID:9395504). Refolding requires Hsc70/Hdj-1. The term 'protein folding' is acceptable as a broad biological process annotation since HSPH1 participates in the protein folding pathway (by handing off substrates to the Hsc70/Hdj-1 refolding machinery), but its direct activity is holding, not folding. As a NEF, HSPH1 also accelerates Hsp70 cycling which supports the overall protein folding process (deep research review, HSPH1-deep-research-falcon.md). Reason: HSPH1 participates in the protein folding pathway by preventing aggregation and maintaining substrates in a folding-competent state for subsequent refolding by Hsc70/Hdj-1. The BP term 'protein folding' is broadly acceptable but HSPH1 is a holdase, not a foldase, so this is kept as non-core. Its direct role is prevention of aggregation rather than active folding. Supporting Evidence: PMID:9395504 hsp110 is highly efficient in selectively recognizing denatured proteins and maintaining them in a soluble, folding-competent state PMID:9395504 hsp110-bound proteins can then be refolded by the addition of rabbit reticulocyte lysate or hsc70 and Hdj-1, whereas Hdj-1 does not itself function as a co-chaperone in folding with hsp110 |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProtKB-KW:KW-0547 (Nucleotide-binding) keyword mapping. HSPH1 belongs to the Hsp70 superfamily and possesses the conserved nucleotide-binding domain (NBD). This is correct but overly general; ATP binding (GO:0005524) is more specific and is already annotated. Reason: Nucleotide binding is correct for HSPH1, which has a conserved Hsp70-type nucleotide-binding domain. While more general than the co-annotated GO:0005524 (ATP binding), the IEA mapping from UniProt keyword is valid. Both annotations can coexist since the IEA is broader. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA annotation from InterPro:IPR013126 (Hsp_70_fam) and UniProtKB-KW:KW-0067 (ATP-binding). HSPH1 has a conserved Hsp70-type nucleotide-binding domain and binds ATP. While Hsp110 family members have greatly reduced ATPase activity compared to canonical Hsp70s, they do bind ATP, which is important for their NEF function. Reason: ATP binding is a core property of HSPH1. The Hsp110 family binds ATP through their conserved NBD. UniProt keywords and InterPro domain classification both support this annotation. ATP binding is required for the NEF function of HSPH1. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation from UniProtKB subcellular location vocabulary mapping (SL-0086). UniProt explicitly states cytoplasm localization for HSPH1 (by similarity to human Q92598). This is the primary localization and is consistent with its chaperone/NEF functions. Reason: Cytoplasm is the primary subcellular localization for HSPH1. UniProt annotation (by similarity) and the protein's established cytoplasmic functions support this. Supporting Evidence: PMID:9395504 hsp110 is one of the principal molecular chaperones of mammalian cells |
| GO:0006950 response to stress | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA-inferred involvement in response to stress. HSPH1 is a heat shock protein whose expression is upregulated under stress conditions. UniProt keywords include 'Stress response'. This is correct but very general; the more specific term GO:0034605 (cellular response to heat) is already annotated with IDA evidence. Reason: Response to stress is valid for this heat shock protein but is very general. The more specific IDA-supported annotation to GO:0034605 (cellular response to heat) captures the core stress response function. Keeping this broader IEA annotation as non-core since it adds no information beyond the specific IDA annotation. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro-inferred ATP hydrolysis activity from IPR013126 (Hsp_70_fam). While HSPH1 belongs to the Hsp70 superfamily and has the conserved ATPase domain architecture, Hsp110 family members have greatly reduced intrinsic ATPase activity compared to canonical Hsp70 chaperones. The deep research review (HSPH1-deep-research-falcon.md) emphasizes that HSPH1 functions primarily as a NEF rather than an ATPase. The ATPase annotation from the broad Hsp70 family InterPro entry is misleading for this diverged subfamily. Reason: Hsp110 family members have significantly reduced ATPase activity compared to canonical Hsp70 proteins. The InterPro family IPR013126 covers the entire Hsp70 superfamily, and while the domain architecture is conserved, Hsp110 members have diverged to function primarily as holdases and NEFs rather than as ATPases. Annotating HSPH1 with GO:0016887 (ATP hydrolysis activity) overstates its catalytic function. The core molecular functions are holdase chaperone activity and NEF activity (GO:0000774). |
| GO:0031249 denatured protein binding | IDA PMID:9395504 Hsp110 protects heat-denatured proteins and confers cellular... | MODIFY | Summary: IDA annotation based on Oh et al. 1997, which demonstrated that Hsp110 is highly efficient at recognizing heat-denatured proteins and maintaining them in a soluble, folding-competent state. This is a genuine holdase chaperone function. GO:0031249 is being obsoleted (go-ontology#30962). The appropriate replacement is GO:0044183 (protein folding chaperone) as a placeholder, with the caveat that HSPH1 is a holdase, not a foldase, and a more specific holdase term is needed (go-ontology#30552). Reason: GO:0031249 (denatured protein binding) is being obsoleted. The experimental evidence from PMID:9395504 clearly demonstrates holdase chaperone activity: Hsp110 prevents aggregation of heat-denatured proteins and maintains them in a folding-competent state. GO:0044183 (protein folding chaperone) is the closest available replacement MF term, used as a placeholder until a specific holdase chaperone activity term is created (go-ontology#30552). Note that HSPH1 does NOT refold proteins itself; refolding requires Hsc70/Hdj-1. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:9395504 hsp110 is highly efficient in selectively recognizing denatured proteins and maintaining them in a soluble, folding-competent state and is significantly more efficient in performing this function than is hsc70 PMID:9395504 hsp110-bound proteins can then be refolded by the addition of rabbit reticulocyte lysate or hsc70 and Hdj-1, whereas Hdj-1 does not itself function as a co-chaperone in folding with hsp110 |
| GO:0034605 cellular response to heat | IDA PMID:9395504 Hsp110 protects heat-denatured proteins and confers cellular... | ACCEPT | Summary: IDA annotation based on Oh et al. 1997, which demonstrated that overexpression of Hsp110 in vivo conferred substantial heat resistance to both Rat-1 and HeLa cells. This is a core biological process for HSPH1 as a heat shock protein. Reason: Well-supported by direct experimental evidence from PMID:9395504 showing that Hsp110 overexpression confers thermoresistance. HSPH1 is one of the primary heat shock proteins in mammalian cells, and cellular response to heat is a core biological process. Supporting Evidence: PMID:9395504 the overexpression in vivo of hsp110 conferred substantial heat resistance to both Rat-1 and HeLa cells PMID:9395504 hsp110 is one of the principal molecular chaperones of mammalian cells and represents a newly identified component of the primary protection/repair pathway for denatured proteins and thermotolerance expression in vivo |
| GO:0000774 adenyl-nucleotide exchange factor activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation transferred from human HSPH1 (Q92598). UniProt describes HSPH1 as acting as a nucleotide-exchange factor (NEF) for HSPA1A and HSPA1B, promoting the release of ADP thereby triggering substrate release (by similarity to mouse Q61699 and human Q92598). This is one of the two core molecular functions of Hsp110 family members. The deep research review (HSPH1-deep-research-falcon.md) confirms that HSPH1 operates as a NEF for cytosolic Hsp70s, binding the Hsp70 NBD to catalyze ADP-to-ATP exchange. Reason: NEF activity is a core molecular function of the Hsp110 family. While the evidence for Chinese hamster HSPH1 specifically is by similarity (ISS), the NEF function is well-conserved across mammalian Hsp110 orthologs and is supported by UniProt annotation (by similarity to Q61699 mouse and Q92598 human). This represents one of the two principal molecular functions of HSPH1 (the other being holdase activity). |
| GO:0044183 protein folding chaperone | IDA PMID:9395504 Hsp110 protects heat-denatured proteins and confers cellular... | NEW | Summary: Proposed new annotation as the replacement MF term for the obsoleting GO:0031249. PMID:9395504 provides direct experimental evidence that Hsp110 functions as a chaperone that prevents aggregation of denatured proteins and maintains them in a folding-competent state. This is a holdase chaperone function (placeholder annotation pending creation of a specific holdase term per go-ontology#30552). Reason: This annotation replaces the obsoleting GO:0031249 (denatured protein binding) with the closest available MF term. HSPH1 is a holdase chaperone that binds denatured proteins to prevent aggregation. GO:0044183 is a placeholder until a specific holdase chaperone activity term is created (go-ontology#30552). Supporting Evidence: PMID:9395504 hsp110 is highly efficient in selectively recognizing denatured proteins and maintaining them in a soluble, folding-competent state |
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Download this section (compressed HTML)Q: Does Chinese hamster HSPH1 have the same NEF activity for Hsp70 as the mouse and human orthologs? The ISS annotation is based on similarity but has not been directly demonstrated for the Chinese hamster protein.
Suggested experts: Subjeck JR
Q: What is the intrinsic ATPase activity level of HSPH1? While Hsp110 family members are known to have reduced ATPase activity compared to canonical Hsp70, the exact level for Chinese hamster HSPH1 has not been characterized.
Suggested experts: Subjeck JR
Experiment: In vitro nucleotide exchange assay using purified Chinese hamster HSPH1 and Hsp70 (HSPA1A). Measure ADP release rates from Hsp70 in the presence and absence of HSPH1 using fluorescent nucleotide analogs.
Hypothesis: Chinese hamster HSPH1 functions as a NEF for hamster Hsp70 family members, similar to the characterized function of mouse and human orthologs.
Type: biochemical assay
Experiment: Comparative ATPase assay measuring the rate of ATP hydrolysis by purified HSPH1 versus HSPA1A using a malachite green phosphate detection assay.
Hypothesis: HSPH1 has significantly lower intrinsic ATPase activity compared to canonical Hsp70 family members.
Type: biochemical assay
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