hsp-110 (ORF C30C11.4) encodes the C. elegans member of the HSP110/HSPH subfamily of the Hsp70 chaperone superfamily, orthologous to yeast Sse1/Sse2 and human HSPH1/HSPA4/ HSPA4L (apg-1). Like other HSP110 proteins it is a cytosolic, ATP-binding relative of Hsp70 that acts as a nucleotide-exchange factor (NEF) for canonical Hsp70 chaperones: its ATP-loaded nucleotide-binding domain, together with a three-helix-bundle domain, clamps the Hsp70 nucleotide-binding domain and drives ADP release, resetting the Hsp70 ATPase/folding cycle. Unlike canonical Hsp70s, HSP110 does not depend on its own ATP hydrolysis for this activity and can additionally bind non-native polypeptides directly (holdase activity). In C. elegans, HSP-110 operates within the cytosolic chaperone and disaggregation network together with Hsp70 and Hsp40/DnaJ partners to limit the accumulation of misfolded, aggregation-prone proteins; loss of HSP-110 increases aggregation of a misfolding-prone protein in neurons. As an HSF-1-regulated heat-shock protein it also contributes to stress resistance and to the extended lifespan of insulin/IGF-1-signaling mutants.
Definition: Binding to an unfolded or misfolded protein to prevent its aggregation without actively catalyzing refolding. The holdase maintains the client protein in a soluble, folding-competent state. This is mechanistically distinct from foldase activity (GO:0044183) and from carrier-holdase activity (GO:0140309).
Justification: hsp-110: beyond its nucleotide-exchange activity for Hsp70, HSP110-family proteins bind non-native polypeptides directly and keep them soluble for Hsp70-dependent refolding; worm hsp-110 (C30C11.4) RNAi increases aggregation of misfolding-prone G85R SOD1 in neurons (PMID:19165329). That RNAi phenotype is necessity evidence that the annotated NEF activity (GO:0000774) could also explain, so the direct substrate-holding arm rests mainly on the HSP110-family biochemistry and remains to be shown for the worm protein itself. Obsolete GO:0051082 captured binding only; GO:0044183 requires assisting folding, and GO:0140309 (relabelled 'unfolded protein holdase activity') keeps a carrier-specific definition requiring escort to an acceptor molecule or location, which is not demonstrated here. See go-ontology#30552.
Parent term: molecular_function
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000774 adenyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. HSP-110 is the C. elegans HSP110-family nucleotide-exchange factor for Hsp70. This IBA is well grounded: the phylogenetic reference set includes yeast Sse1/Sse2 and human HSPH1, for which NEF activity is directly established. Reason: HSP110 proteins are the principal cytosolic NEFs for Hsp70; the ATP-loaded HSP110 NBD engages the Hsp70 NBD and drives ADP release. This is the defining, informative molecular function of the gene and should be retained as core. Supporting Evidence: PMID:16688211 acts as an efficient nucleotide exchange factor (NEF) for both yeast cytosolic Hsp70s, Ssa1p and Ssb1p. The mechanism involves formation of a stable nucleotide-sensitive complex, but does not require ATP hydrolysis by Sse1p PMID:18555782 the NBD of Sse1p is ATP bound, and together with the 3HBD it embraces the NBD of Hsp70, inducing opening and the release of bound ADP from Hsp70. Mutations that abolish NEF activity are lethal, thus defining nucleotide exchange on Hsp70 as an essential function of Sse1p |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically propagated nuclear localization. HSP110-family proteins are primarily cytosolic; some mammalian HSPH1 can partition to the nucleus, but there is no direct C. elegans evidence for a nuclear pool of HSP-110. Reason: Retain as a possible minor/shuttling location inherited from the family tree, but it is not the site of the core function; the cytosol is where HSP-110 acts on Hsp70. |
| GO:0006457 protein folding | IBA GO_REF:0000033 | ACCEPT | Summary: HSP-110 participates in the cytosolic protein-folding process as the Hsp70 NEF; its NEF activity stimulates Hsp70-mediated refolding of denatured substrates. Reason: Valid and central biological process for an Hsp70 co-chaperone/NEF; consistent with the experimental IMP protein-folding annotation from the worm and with the conserved family mechanism. Supporting Evidence: PMID:16688211 The NEF activity of Sse1p stimulates in vitro Ssa1p-mediated refolding of thermally denatured luciferase |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Core location. HSP110 proteins are cytosolic Hsp70 relatives, and the worm HSP-110 acts on cytosolic Hsp70. Reason: The cytosol is the compartment where HSP-110 performs its NEF function; well supported at the family level and consistent with worm proteostasis assays in cytoplasm. Supporting Evidence: PMID:16688211 The Hsp110 proteins, exclusively found in the eukaryotic cytosol |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: HSP-110 retains the Hsp70-family nucleotide-binding domain and binds ATP; ATP loading of its NBD is functionally required for NEF activity (the ATP-bound NBD clamps the Hsp70 NBD to release ADP). Reason: ATP/adenyl-nucleotide binding is genuine and mechanistically essential for HSP-110 NEF function, not a spurious fold-based call. Supporting Evidence: PMID:18555782 the NBD of Sse1p is ATP bound, and together with the 3HBD it embraces the NBD of Hsp70, inducing opening and the release of bound ADP from Hsp70 |
| GO:0006950 response to stress | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Generic stress-response term from ARBA. HSP-110 is a heat-shock protein and HSF-1 transcriptional target, so involvement in the stress response is correct but uninformatively broad relative to the specific proteostasis roles captured elsewhere. Reason: True but too general; the specific and better-supported terms (response to topologically incorrect protein, protein folding) convey the actual role. Keep as a broad, non-core annotation. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Propagated from the generic Hsp70 ATPase fold. HSP110-family proteins have only weak, atypical ATPase activity, and their defining NEF mechanism explicitly does NOT require ATP hydrolysis by HSP110; HSP110 also does not use the canonical Hsp70 nucleotide-driven allosteric cycle. Reason: The term is not categorically impossible (HSP110 binds and may slowly turn over ATP), but attributing a functional ATP hydrolysis activity over-states the biochemistry: it is an electronic call from the shared Hsp70 domain, whereas the characterized HSP110 role is NEF and holdase, with ATP binding (not hydrolysis) being the load-bearing property. Flag as likely over-annotation rather than remove outright. Supporting Evidence: PMID:16688211 The mechanism involves formation of a stable nucleotide-sensitive complex, but does not require ATP hydrolysis by Sse1p PMID:18555782 does not employ the nucleotide-dependent allostery and peptide-binding mode of canonical Hsp70s |
| GO:0006457 protein folding | IMP PMID:22242008 A genetic screening strategy identifies novel regulators of ... | ACCEPT | Summary: Experimental WormBase annotation. In a genome-wide RNAi screen, C30C11.4 (hsp-110) was one of six chaperone-class genes among the polyglutamine (Q35/Q37) aggregation modifiers (a Class A strong modifier), linking it to the muscle-cell protein-folding environment. Reason: Experimental (IMP) annotation supported by the screen; consistent with HSP-110's role as an Hsp70 NEF in cytosolic protein folding. Deferred to the WormBase curator who assessed the full dataset. Supporting Evidence: PMID:22242008 F08H9.3; cyn-11; cyn-12; C30C11.4; dnj-22; phb-2 |
| GO:0035966 response to topologically incorrect protein | IMP PMID:19165329 An ALS-linked mutant SOD1 produces a locomotor defect associ... | ACCEPT | Summary: Experimental WormBase annotation and a core biological role. RNAi and the gk533 loss-of-function allele of hsp-110/C30C11.4 strongly increase aggregation of neuronally expressed misfolding-prone mutant human SOD1(G85R); HSP-110 acts here with an Hsp70 (stc-1) and a DnaJ (dnj-19), i.e. the metazoan Hsp70-Hsp40-Hsp110 anti-aggregation machinery. Reason: Directly supported experimental annotation for this gene; captures HSP-110's in vivo function in handling misfolded (topologically incorrect) proteins. Supporting Evidence: PMID:19165329 including an Hsp110 (C30C11.4), a DnaJ (A2) (dnj-19), an Hsp70 (stc-1), and a neuron specific Hsp16 (F08H9.4) PMID:19165329 Three of these were validated as strongly increasing aggregation when mutant alleles were crossed with G85R-YFP |
| GO:0008340 determination of adult lifespan | IGI PMID:14668486 Regulation of longevity in Caenorhabditis elegans by heat sh... | KEEP AS NON CORE | Summary: Experimental IGI annotation. HSF-1-target molecular chaperones, when down-regulated, shorten the extended lifespan of long-lived insulin/IGF-1-signaling mutants; the WormBase annotation records a genetic interaction of hsp-110 with age-1 (WBGene00000090). This is a pleiotropic, downstream organismal consequence of HSP-110's chaperone activity rather than its core molecular function. Reason: Retain as a genuine experimental (genetic-interaction) annotation - do not remove - but classify as non-core: lifespan determination reflects HSP-110's contribution to the proteostasis/stress network, not a distinct molecular activity. Cached reference is abstract-only; deferred to the WormBase curator who read the full text. Supporting Evidence: PMID:14668486 Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals |
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Download this section (compressed HTML)Q: Which C. elegans Hsp70 (HSP-1, STC-1, or HSP-70) and which J-domain/Hsp40 proteins form the physiological HSP-110-dependent disaggregation machine in each tissue?
Suggested experts: C. elegans proteostasis biologists, Hsp70/Hsp110 chaperone biochemists
Q: Is HSP-110 required to dissolve pre-formed aggregates, or only to prevent their formation, in worm neurons and muscle?
Suggested experts: Protein-aggregation/disaggregase biologists
Experiment: Affinity-purify endogenously tagged HSP-110 from C. elegans lysate and identify Hsp70, Hsp40/J-protein, and client partners to define the worm disaggregation network and native substrates.
Type: Affinity purification / mass spectrometry
Experiment: Engineer NEF-dead, ATPase-dead, and substrate-binding-dead hsp-110 alleles and test each for rescue of aggregation/disaggregation and lifespan phenotypes to dissect which molecular property (nucleotide exchange, ATP hydrolysis, holdase) is required in vivo.
Type: Separation-of-function genetics
Experiment: Reconstitute disaggregation of aggregated model substrates with purified worm HSP-110, Hsp70, and Hsp40 to test whether HSP-110 is required and rate-limiting for the reaction.
Type: In vitro disaggregation reconstitution
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether C. elegans HSP-110 is genetically and biochemically required for Hsp70/Hsp40-mediated protein DISAGGREGATION in vivo, and the identity of its physiological worm Hsp70 (HSP-1 vs STC-1 vs HSP-70) and J-protein/Hsp40 partners in that reaction, are undetermined.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: It is established that HSP-110 is an HSP110-family Hsp70 NEF (conserved from yeast Sse1 to human HSPH1) and that in neurons its loss (RNAi and the gk533 allele) increases aggregation of misfolding-prone SOD1 alongside an Hsp70 (stc-1) and a DnaJ (dnj-19). What is NOT established for the worm is a reconstituted or genetically defined Hsp70-Hsp40-Hsp110 disaggregase, its obligate partner set, and whether HSP-110 is required for active dissolution of pre-formed aggregates (as opposed to preventing their formation).
Significance: Metazoan protein disaggregation depends on a cooperative Hsp70-Hsp40-Hsp110 system. Defining the worm partners and the requirement for HSP-110 would connect its molecular NEF activity to organismal proteostasis and neuroprotection, and clarify which chaperone axis to target in C. elegans neurodegeneration models.
What would resolve it: Tissue-specific hsp-110 loss-of-function combined with aggregation/disaggregation reporters and photoconvertible aggregation-clearance assays; affinity-purification/mass-spectrometry of tagged HSP-110 from worm lysate to define Hsp70/J-protein partners; in vitro reconstitution of a worm disaggregase.
Provenance (the field's own admissions):
Gap: The endogenous C. elegans client repertoire of HSP-110 is undefined: which native metastable proteins depend on HSP-110 NEF/holdase activity, and in which tissues, is unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: HSP-110 demonstrably modifies aggregation of heterologous, aggregation-prone reporters (polyglutamine and mutant human SOD1) and, at the family level, HSP110 NEF activity stimulates Hsp70-mediated refolding of denatured model substrates such as luciferase. No endogenous physiological worm client of HSP-110 has been mapped.
Significance: Client identity determines where HSP-110 activity is rate-limiting for proteostasis and which phenotypes (muscle, neuron, germline, aging) are mechanistically downstream of the NEF function.
What would resolve it: Chaperone-client capture (e.g. interactomics of tagged HSP-110, or aggregate proteomics in hsp-110 loss-of-function) to enumerate native substrates.
Provenance (the field's own admissions):
Gap: Whether HSP-110's own weak/atypical ATPase activity, and any Hsp70-independent holdase function, have a physiological role in C. elegans is untested.
OPEN BIOLOGY MF_DARK
What is known: The defining HSP110 NEF mechanism requires ATP BINDING but not ATP hydrolysis by HSP110, and HSP110 does not use the canonical Hsp70 nucleotide-driven allosteric peptide-binding cycle; direct substrate binding by Hsp110 has been observed in vitro. The in vivo relevance of HSP-110 ATP hydrolysis and of a standalone holdase mode in the worm has not been probed.
Significance: Resolving this would settle whether the IEA-propagated ATP hydrolysis activity is functionally meaningful for HSP-110 or a fold-based over-annotation, and whether HSP-110 contributes to proteostasis independently of Hsp70.
What would resolve it: Structure-guided separation-of-function alleles (NEF-dead vs ATPase-dead vs substrate-binding-dead) tested for rescue of hsp-110 proteostasis phenotypes in vivo, plus in vitro ATPase and holdase assays on purified worm HSP-110.
Provenance (the field's own admissions):
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