HSP110c

HSP110c (PF3D7_0708800) is an essential cytosolic Hsp110-family chaperone that maintains proteostasis in P. falciparum during the febrile episodes of malaria infection, functioning as a holdase that prevents aggregation of the parasite's asparagine repeat-rich proteome at elevated temperatures (PMID:23250440). Gene knockout is lethal and conditional knockdown parasites die rapidly upon heat shock, unable to suppress aggregation of asparagine-repeat clients such as PFI1155w, while human and yeast orthologs are far less effective at this task—establishing HSP110c as specifically adapted to the parasite's repeat-rich proteome (PMID:23250440). Biochemically, recombinant HSP110c is heat-stable, possesses intrinsic ATPase activity, self-associates, and is upregulated under heat stress (PMID:26083397); it suppresses protein aggregation in vitro and binds the canonical cytosolic chaperone PfHsp70-1 in a nucleotide-dependent manner consistent with a nucleotide exchange factor role (PMID:26894764). Its unique rigid linker segment is the structural determinant that restricts HSP110c to holdase (rather than refoldase) function, confers thermal stability, and tunes client binding, ATPase activity, ATP-binding affinity, and co-chaperone (PfHsp40) interactions, as shown by linker-switch mutants that swap in the flexible linkers of PfHsp70-1 or DnaK (PMID:33741370, PMID:34141839). Beyond these findings, no further mechanistic detail has been characterized in the available corpus.

1. 2012 High

   Whether P. falciparum requires a dedicated chaperone to survive febrile temperatures was unresolved; this work established HSP110c as essential for proteostasis by protecting the parasite's asparagine repeat-rich proteome from heat-induced aggregation.

   Evidence co-expression aggregation assay in mammalian cells, conditional knockdown and gene knockout in P. falciparum with immunofluorescence aggregation readout

   PMID:23250440

   Open questions at the time

   • the full repertoire of endogenous asparagine-repeat clients was not defined
   • structural basis for the parasite ortholog's superior anti-aggregation activity not resolved
2. 2015 Medium

   To determine the intrinsic biochemical properties underlying its chaperone role, recombinant HSP110c was shown to be heat-stable, to have ATPase activity, to self-associate, and to be heat-inducible in culture.

   Evidence recombinant protein ATPase, thermal stability and self-association assays plus heat-stress expression analysis

   PMID:26083397

   Open questions at the time

   • functional consequence of self-association in vivo not established
   • ATPase cycle not linked to a defined client-binding mechanism
3. 2016 High

   Whether HSP110c acts autonomously or cooperatively was addressed by showing it has independent holdase activity and binds PfHsp70-1 nucleotide-dependently, positioning it as a candidate nucleotide exchange factor for the canonical Hsp70.

   Evidence in vitro aggregation suppression assay, co-immunoaffinity chromatography, and surface plasmon resonance

   PMID:26894764

   Open questions at the time

   • NEF activity inferred from nucleotide-dependent binding but not directly measured as nucleotide exchange kinetics
   • cellular role of the PfHsp70-1 interaction not tested by perturbation
4. 2021 High

   The structural determinant restricting HSP110c to holdase function was identified: linker-switch mutants demonstrated that its rigid linker (versus the flexible linker of canonical Hsp70s) governs conformation, client binding, holdase activity, ATPase activity, ATP-binding affinity, and PfHsp40 interaction, and prevents refoldase activity.

   Evidence linker-switch site-directed mutagenesis with circular dichroism, fluorescence spectroscopy, ATPase and client-binding assays, and SPR

   PMID:33741370 PMID:34141839

   Open questions at the time

   • the linker's role in intact parasites not tested by allelic replacement
   • high-resolution structure of the full-length protein not determined

• It remains unknown how HSP110c's holdase and putative nucleotide-exchange functions are integrated within the parasite cytosolic chaperone network in vivo and which endogenous clients it engages during a febrile cycle.
• in vivo client interactome undefined
• no structural model of client or co-chaperone complexes
• NEF activity not demonstrated by functional exchange assay