hsp-110 (C. elegans) — research notes

Gene: hsp-110 / ORF C30C11.4 / WormBase WBGene00016250
UniProt: Q05036 (HS110_CAEEL), 776 aa, chromosome III.
Product: Heat shock protein 110 (HSP110 / HSPH-family Hsp70 relative).

Identity / family (KNOWN)

Molecular function (KNOWN at family level; INFERRED for worm)

HSP110-family proteins are the principal cytosolic nucleotide-exchange factors (NEFs) for
Hsp70. Established biochemically/structurally in yeast (Sse1p) and conserved across
eukaryotes:

Implications for the GO annotations:
- ATP binding (GO:0005524) is genuine and functionally required: Hsp110's own NBD must be
ATP-loaded to embrace and open the Hsp70 NBD PMID:18555782.
- ATP hydrolysis (GO:0016887), in contrast, is not required for the defining NEF
activity, and Hsp110 "does not employ the nucleotide-dependent allostery and peptide-binding
mode of canonical Hsp70s" PMID:18555782.
So the IEA ATP hydrolysis activity (propagated from the generic Hsp70 fold) is an
over-annotation relative to the characterized mechanism (weak/atypical ATPase; hydrolysis
dispensable).
- Beyond NEF, Hsp110 also has intrinsic holdase / substrate-binding activity ("direct
interactions of substrate with Sse1p may support Hsp70-assisted protein folding"
PMID:18555782), and its NEF activity stimulates Hsp70-mediated refolding of denatured
substrate ("The NEF activity of Sse1p stimulates in vitro Ssa1p-mediated refolding of
thermally denatured luciferase" PMID:16688211).

Worm-specific biological role (KNOWN — experimental)

  1. Prevents aggregation of a misfolding-prone protein in neurons in vivo (disaggregase/
    holdase partner of the Hsp70 machine).     In a pan-neuronal mutant human SOD1(G85R) ALS model,
    an RNAi screen for modifiers of aggregation found that knockdown of a set of chaperones —
    "including an Hsp110 (C30C11.4), a DnaJ (A2) (dnj-19), an Hsp70 (stc-1), and a neuron specific
    Hsp16 (F08H9.4)" — strongly increased SOD1 inclusion formation PMID:19165329. The effect was confirmed with the loss-of-function allele gk533 (Table 2:
    "C30C11.4 ... homolog to human apg-1 (a heat shock 110 kDa protein) 3 gk533 ++", strong
    increase of inclusions). This co-set (Hsp110 + Hsp40/DnaJ + Hsp70) is exactly the metazoan
    Hsp70–Hsp40–Hsp110 disaggregation machinery, giving in vivo support for
    GO:0035966 (response to topologically incorrect protein). UniProt records the disruption
    phenotype: "RNAi-mediated knockdown in a sod-1 mutant background results in increased
    aggregation of denatured proteins in neurons" [file:worm/hsp-110/hsp-110-uniprot.txt].

  2. Modifier of proteostasis / polyglutamine folding (protein folding, IMP). In a genome-wide
    RNAi screen in body-wall muscle, C30C11.4 was one of six chaperone-class genes among the polyQ
    (Q35/Q37) aggregation modifiers ("Protein Folding and transport ... Chaperone (6) F08H9.3;
    cyn-11; cyn-12; C30C11.4; dnj-22; phb-2") whose knockdown suppressed polyQ aggregation
    PMID:22242008. It was a Class A (strong,
    Q35+Q37) modifier. This is the basis of the WormBase IMP GO:0006457 (protein folding)
    annotation. (Note the direction: here knockdown suppresses aggregation, whereas in the
    neuronal SOD1 model knockdown increases aggregation — i.e. the readout is model-dependent,
    but both link hsp-110 to the folding/aggregation environment.)

  3. Contributes to longevity of insulin/IGF-1-signaling (ILS) mutants (determination of adult
    lifespan, IGI).     Morley & Morimoto showed that "Down-regulation of individual molecular
    chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant
    but not wild-type animals" PMID:14668486. The WormBase IGI annotation records a genetic interaction with
    WB:WBGene00000090 = age-1 (PI3K, an ILS long-lived mutant background). This paper is
    abstract-only in our cache (full_text_available: false); the specific hsp-110 result is in the
    full text the curator read. Treated as a real experimental annotation (do not remove); it is a
    pleiotropic/downstream organismal role, not the core molecular function → KEEP_AS_NON_CORE.

Localization (KNOWN at family level)

NOT known (candidate knowledge gaps)

Deep research