Copper pathways in Plasmodium falciparum infected erythrocytes indicate an efflux role for the copper P-ATPase

Dominique Rasoloson, Lirong Shi, Curtis R. Chong, Bjorn F. Kafsack, David J. Sullivan

Research output: Contribution to journalArticlepeer-review

Abstract

Copper, like iron, is a transition metal that can generate oxygen radicals by the Fenton reaction. The Plasmodium parasite invades an erythrocyte host cell containing 20 μM copper, of which 70 % is contained in the Cu/Zn SOD (cuprozinc superoxide dismutase). In the present study, we follow the copper pathways in the Plasmodium-infected erythrocyte. Metal-determination analysis shows that the total copper content of Percoll-purified trophozoite-stage- infected erythrocytes is 66 % that of uninfected erythrocytes. This decrease parallels the decrease seen in Cu/Zn SOD levels in parasite-infected erythrocytes. Neocuproine, an intracellular copper chelator, arrests parasites at the ring-to-trophozoite stage transition and also specifically decreases intraparasitic levels of Cu/Zn SOD and catalase. Up to 150 μM BCS (2,9-dimethyl-4,7-diphenyl-1,10-phenanthrolinedisulphonic acid), an extracellular copper chelator, has no effect on parasite growth. We characterized a single copy PfCuP-ATPase (Plasmodium falciparum copper P-ATPase) transporter, which, like the Cryptosporidium parvum copper P-ATPase, has a single copper-binding domain: 'Met-Xaa-Cys-Xaa-Xaa-Cys'. Recombinant expression of the N-terminal metal-binding domain reveals that the protein specifically binds reduced copper. Transcription of the PfCuP-ATPase gene is the highest at late ring stage/early trophozoite, and is down-regulated in the presence of neocuproine. Immunofluorescence and electron microscopy indicate the transporter to be both in the parasite and on the erythrocyte membrane. Both the decrease in total copper and the location of the PfCuP-ATPase gene indicate a copper-efflux pathway from the infected erythrocyte.

Original languageEnglish (US)
Pages (from-to)803-811
Number of pages9
JournalBiochemical Journal
Volume381
Issue number3
DOIs
StatePublished - Aug 1 2004

Keywords

  • Chaperone
  • Chelator
  • Copper
  • Neocuproine
  • P-ATPase transporter
  • Plasmodium falciparum

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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