The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Wider, Diana; Péli-Gulli, Marie-Pierre; Briand, Pierre-André; Tatu, Utpal; Picard, Didier

doi:10.1016/j.molbiopara.2008.12.011

Scientific article

English

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Contributors

Wider, Diana; Péli-Gulli, Marie-Pierre; Briand, Pierre-André; Tatu, Utpal; Picard, Didier

Published in

Molecular and biochemical parasitology, vol. 164, no. 2, p. 147-152

Publication date

2009

Abstract

Developing novel drugs against the unicellular parasite Plasmodium is complicated by the paucity of simple screening systems. Heat-shock proteins are an essential class of proteins for the parasite's cyclical life style between different cellular milieus and temperatures. The molecular chaperone Hsp90 assists a large variety of proteins, but its supporting functions for many proteins that are important for cancer have made it into a well-studied drug target. With a better understanding of the differences between Hsp90 of the malarial parasite and Hsp90 of its human host, new therapeutic options might become available. We have generated a set of isogenic strains of the budding yeast Saccharomyces cerevisiae where the essential yeast Hsp90 proteins have been replaced with either of the two human cytosolic isoforms Hsp90α or Hsp90β, or with Hsp90 from Plasmodium falciparum (Pf). All strains express large amounts of the Flag-tagged Hsp90 proteins and are viable. Even though the strain with Pf Hsp90 grows more poorly, it provides a tool to reconstitute additional aspects of the parasite Hsp90 complex and its interactions with substrates in yeast as a living test tube. Upon exposure of the set of Hsp90 test strains to the two Hsp90 inhibitors radicicol (Rd) and geldanamycin (GA), we found that the strain with Pf Hsp90 is relatively more sensitive to GA than to Rd compared to the strains with human Hsp90's. This indicates that this set of yeast strains could be used to screen for new Pf Hsp90 inhibitors with a wider therapeutic window.

Keywords

Malaria
Hsp90
Screen
Drug
Saccharomyces cerevisiae
Pathogen

UNIGE affiliation entities

Faculté des sciences / Section de biologie / Département de biologie cellulaire

Citation (ISO format)

WIDER, Diana et al. The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities. In: Molecular and biochemical parasitology, 2009, vol. 164, n° 2, p. 147–152. doi: 10.1016/j.molbiopara.2008.12.011

Article (Published version)

Identifiers

PID : unige:4468
DOI : 10.1016/j.molbiopara.2008.12.011

Journal ISSN

0166-6851

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Creation

01/12/2009 08:55:00

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01/12/2009 08:55:00

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14/03/2023 15:18:56

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14/03/2023 15:18:56

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29/10/2024 12:43:24

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Contributors

Published in

Publication date

Abstract

Keywords

UNIGE affiliation entities

Citation (ISO format)

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Journal ISSN

Technical informations

Creation

First validation

Update

Status update

Last indexation