Heat Shock Protein 90 Function Is Essential for Plasmodium falciparum Growth in Human Erythrocytes

Gowrishankar Banumathy, Varsha Singh, Soundara Raghavan Pavithra, Utpal Tatu (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

197 Citations (Scopus)
3 Downloads (Pure)

Abstract

Hsp90 is important for normal growth and development in eukaryotes. Together with Hsp70 and other accessory proteins, Hsp90 not only helps newly synthesized proteins to fold but also regulates activities of transcription factors and protein kinases. Although the gene coding for heat shock protein 90 from Plasmodium falciparum (PfHsp90) has been characterized previously, there is very little known regarding its function in the parasite. We have analyzed PfHsp90 complexes and addressed its role in parasite life cycle using Geldanamycin (GA), a drug known to interfere with Hsp90 function. Sedimentation analysis and size exclusion chromatography showed PfHsp90 to be in 11 s20,w complexes of ∼300 kDa in size. Similar to the hetero-oligomeric complexes of Hsp90 in mammals, PfHsp70 was found to be present in PfHsp90 complexes. Homology modeling revealed a putative GA-binding pocket at the amino terminus of PfHsp90. The addition of GA inhibited parasite growth with LD50 of 0.2 μM. GA inhibited parasite growth by arresting transition from Ring to trophozoite. Transition from trophozoite to schizonts and reinvasion of new erythrocytes were less significantly affected. While inducing the synthesis of PfHsp70 and PfHsp90, GA did not significantly alter the pattern of newly synthesized proteins. Pre-exposure to heat shock attenuated GA-mediated growth inhibition, suggesting the involvement of heat shock proteins. Specificity of GA action on PfHsp90 was evident from selective inhibition of PfHsp90 phosphorylation in GA-treated cultures. In addition to suggesting an essential role for PfHsp90 during parasite growth, our results highlight PfHsp90 as a potential drug target to control malaria.

Original languageEnglish
Pages (from-to)18336-18345
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number20
DOIs
Publication statusPublished - 16 May 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Heat Shock Protein 90 Function Is Essential for Plasmodium falciparum Growth in Human Erythrocytes'. Together they form a unique fingerprint.

Cite this