Original Paper

Cell Stress and Chaperones

, Volume 16, Issue 4, pp 389-401

First online:

Plasmodium falciparum encodes a single cytosolic type I Hsp40 that functionally interacts with Hsp70 and is upregulated by heat shock

  • Melissa BothaAffiliated withBiomedical Biotechnology Research Unit, Department of Biochemistry, Microbiology and Biotechnology, Rhodes University
  • , Annette N. ChiangAffiliated withDepartment of Biological Sciences, University of Pittsburgh
  • , Patrick G. NeedhamAffiliated withDepartment of Biological Sciences, University of Pittsburgh
  • , Linda L. StephensAffiliated withBiomedical Biotechnology Research Unit, Department of Biochemistry, Microbiology and Biotechnology, Rhodes University
  • , Heinrich C. HoppeAffiliated withCouncil for Scientific and Industrial Research
  • , Simone KülzerAffiliated withDepartment of Parasitology, Faculty of Biology, Philipps University Marburg
  • , Jude M. PrzyborskiAffiliated withDepartment of Parasitology, Faculty of Biology, Philipps University Marburg
  • , Klaus LingelbachAffiliated withDepartment of Parasitology, Faculty of Biology, Philipps University Marburg
  • , Peter WipfAffiliated withDepartment of Chemistry, University of Pittsburgh
    • , Jeffrey L. BrodskyAffiliated withDepartment of Biological Sciences, University of Pittsburgh
    • , Addmore ShonhaiAffiliated withDepartment of Biochemistry and Microbiology, University of Zululand
    • , Gregory L. BlatchAffiliated withBiomedical Biotechnology Research Unit, Department of Biochemistry, Microbiology and Biotechnology, Rhodes University Email author 

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Abstract

Heat shock protein 70 (Hsp70) and heat shock protein 40 (Hsp40) function as molecular chaperones during the folding and trafficking of proteins within most cell types. However, the Hsp70–Hsp40 chaperone partnerships within the malaria parasite, Plasmodium falciparum, have not been elucidated. Only one of the 43 P. falciparum Hsp40s is predicted to be a cytosolic, canonical Hsp40 (termed PfHsp40) capable of interacting with the major cytosolic P. falciparum-encoded Hsp70, PfHsp70. Consistent with this hypothesis, we found that PfHsp40 is upregulated under heat shock conditions in a similar pattern to PfHsp70. In addition, PfHsp70 and PfHsp40 reside mainly in the parasite cytosol, as assessed using indirect immunofluorescence microscopy. Recombinant PfHsp40 stimulated the ATP hydrolytic rates of both PfHsp70 and human Hsp70 similar to other canonical Hsp40s of yeast (Ydj1) and human (Hdj2) origin. In contrast, the Hsp40-stimulated plasmodial and human Hsp70 ATPase activities were differentially inhibited in the presence of pyrimidinone-based small molecule modulators. To further probe the chaperone properties of PfHsp40, protein aggregation suppression assays were conducted. PfHsp40 alone suppressed protein aggregation, and cooperated with PfHsp70 to suppress aggregation. Together, these data represent the first cellular and biochemical evidence for a PfHsp70–PfHsp40 partnership in the malaria parasite, and furthermore that the plasmodial and human Hsp70–Hsp40 chaperones possess unique attributes that are differentially modulated by small molecules.

Keywords

Aggregation ATPase Codon harmonisation Heat shock protein Malaria Molecular chaperone