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

TitleCopper pathways in Plasmodium falciparum infected erythrocytes indicate an efflux role for the copper P-ATPase.
Publication TypeJournal Article
Year of Publication2004
AuthorsRasoloson D, Shi L, Chong CR, Kafsack BF, Sullivan DJ
JournalBiochem J
Volume381
IssuePt 3
Pagination803-11
Date Published2004 Aug 01
ISSN1470-8728
KeywordsAdenosine Triphosphatases, Amino Acid Sequence, Animals, Arabidopsis Proteins, Caenorhabditis elegans Proteins, Cation Transport Proteins, Chelating Agents, Chromosome Mapping, Copper, DNA, Protozoan, Drosophila Proteins, Erythrocyte Membrane, Erythrocytes, Humans, Mice, Molecular Sequence Data, Open Reading Frames, Phenanthrolines, Plasmodium falciparum, Protozoan Proteins, Saccharomyces cerevisiae Proteins, Sequence Analysis, Protein, Superoxide Dismutase
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 microM 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 microM 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 Crypto-sporidium 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.

DOI10.1042/BJ20040335
Alternate JournalBiochem J
PubMed ID15125686
PubMed Central IDPMC1133890
Grant ListM01 RR000052 / RR / NCRR NIH HHS / United States
R01 AI045774 / AI / NIAID NIH HHS / United States
R01 AI45774-01 / AI / NIAID NIH HHS / United States
RR0052 / RR / NCRR NIH HHS / United States

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