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Plasmodium falciparum heat shock protein 110 stabilizes the asparagine repeat-rich parasite proteome during malarial fevers

1] Howard Hughes Medical Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110, USA [2] Departments of Medicine and Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110, USA [3].
Nature Communications (Impact Factor: 10.74). 12/2012; 3:1310. DOI: 10.1038/ncomms2306
Source: PubMed

ABSTRACT One-fourth of Plasmodium falciparum proteins have asparagine repeats that increase the propensity for aggregation, especially at elevated temperatures that occur routinely in malaria-infected patients. Here we report that a Plasmodium Asn repeat-containing protein (PFI1155w) formed aggregates in mammalian cells at febrile temperatures, as did a yeast Asn/Gln-rich protein (Sup35). Co-expression of the cytoplasmic P. falciparum heat shock protein 110 (PfHsp110c) prevented aggregation. Human or yeast orthologs were much less effective. All-Asn and all-Gln versions of Sup35 were protected from aggregation by PfHsp110c, suggesting that this chaperone is not limited to handling runs of asparagine. PfHsp110c gene-knockout parasites were not viable and conditional knockdown parasites died slowly in the absence of protein-stabilizing ligand. When exposed to brief heat shock, these knockdowns were unable to prevent aggregation of PFI1155w or Sup35 and died rapidly. We conclude that PfHsp110c protects the parasite from harmful effects of its asparagine repeat-rich proteome during febrile episodes.

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    • "Indeed, it has been recently demonstrated that the stability of several Plasmodium proteins depends upon their association with heat shock proteins which act as molecular chaperones [58]. Therefore, recombinant protein expression in the HEK293 system could be further enhanced by the presence of PfHsp110c, which has been proposed to be a protein-stabilizing chaperone [58]. "
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    • "In a strategy similar to that described above, we tagged PfAtg7 with a regulatable fluorescent affinity tag (RFA), an approach that has been successful for regulated protein attenuation in P. falciparum [30], [43]. This construct adds the RFA tag to the C-terminus, which results in the Atg7 protein fused to an attenuable destabilization domain (in addition to GFP and HA), which is stabilized by the presence of the folate analog trimethoprim (TMP) in the growth medium. "
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    PLoS ONE 06/2013; 8(6):e67047. DOI:10.1371/journal.pone.0067047 · 3.23 Impact Factor
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    • "So far only one of our Plasmodium PrDs candidates has been characterized experimentally: PFI115w (Q8I2S1_PLAF7). In agreement with our prediction, the protein aggregates intracellularly when expressed in human cells [82]. Plasmodium chaperones act as cellular capacitors allowing the accumulation of potentially deleterious PrDs, whose presence should therefore provide certain advantage to the organism. "
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