Cell Stress and Chaperones

, Volume 22, Issue 5, pp 707–715 | Cite as

Polymyxin B inhibits the chaperone activity of Plasmodium falciparum Hsp70

  • Tawanda Zininga
  • Ofentse J. Pooe
  • Pertunia B. Makhado
  • Lebogang Ramatsui
  • Earl Prinsloo
  • Ikechukwu Achilonu
  • Heinrich Dirr
  • Addmore Shonhai
Original Paper

Abstract

Heat shock protein 70 (Hsp70) is a molecular chaperone that plays an important role in cellular proteostasis. Hsp70s are also implicated in the survival and pathogenicity of malaria parasites. The main agent of malaria, Plasmodium falciparum, expresses six Hsp70s. Of these, two (PfHsp70-1 and PfHsp70-z) localize to the parasite cytosol. Previously conducted gene knockout studies suggested that PfHsp70-z is essential, and it has been demonstrated that small-molecule inhibitors targeting PfHsp70-1 cause parasite death. For this reason, both PfHsp70-1 and PfHsp70-z are potential antimalarial targets. Two cyclic lipopeptides, colistin and polymyxin B (PMB), have been shown to bind another heat shock protein, Hsp90, inhibiting its chaperone function. In the current study, we investigated the effect of PMB on the structure–function features of PfHsp70-1 and PfHsp70-z. Using surface plasmon resonance analysis, we observed that PMB directly interacts with both PfHsp70-1 and PfHsp70-z. In addition, using circular dichroism spectrometric analysis combined with tryptophan fluorescence measurements, we observed that PMB modulated the secondary and tertiary structures of Hsp70. Furthermore, PMB inhibited the basal ATPase activity and chaperone function of the two Hsp70s. Our findings suggest that PMB associates with Hsp70 to inhibit its function. In light of the central role of Hsp70 in cellular proteostasis and its essential role in the development of malaria parasites in particular, our findings expand the library of small-molecule inhibitors that target this medically important class of molecular chaperones.

Keywords

Heat shock protein Polymyxin B Chaperone Aggregation Heat stress Inhibitor 

Notes

Acknowledgements

This project was supported through a grant (L1/402/14-1) provided to A.S. by the Deutsche Forschungsgemeinschaft (DFG) under the theme, “German–African Cooperation Projects in Infectiology.” We are grateful to the Department of Science and Technology/National Research Foundation (NRF) of South Africa for providing an equipment grant (UID, 75464) and NRF mobility grant (UID, 92598) awarded to A.S., DST/NRF National Nanotechnology Equipment grant awarded to E.P., and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (grant 64788 to H.W.D.) which facilitated the study. T.Z. is a recipient of the Claude Leon fellowship and A.S. is a recipient of a Georg Foster research fellowship awarded by the Alexander von Humboldt Foundation, Germany.

Compliance with ethical standards

Conflict of interest

All the authors declare no conflicts of interest.

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Copyright information

© Cell Stress Society International 2017

Authors and Affiliations

  • Tawanda Zininga
    • 1
  • Ofentse J. Pooe
    • 2
  • Pertunia B. Makhado
    • 1
  • Lebogang Ramatsui
    • 1
  • Earl Prinsloo
    • 3
  • Ikechukwu Achilonu
    • 4
  • Heinrich Dirr
    • 4
  • Addmore Shonhai
    • 1
  1. 1.Department of Biochemistry, School of Mathematical and Natural SciencesUniversity of VendaThohoyandouSouth Africa
  2. 2.Department of Biochemistry, Westville CampusUniversity of KwaZulu-NatalDurbanSouth Africa
  3. 3.Biotechnology Innovation CentreRhodes UniversityGrahamstownSouth Africa
  4. 4.Protein Structure-Function Research Unit, School of Molecular & Cell BiologyUniversity of the WitwatersrandJohannesburgSouth Africa

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