Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance.

TitleMutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance.
Publication TypeJournal Article
Year of Publication2000
AuthorsFidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, Ursos LM, Sidhu AB, Naudé B, Deitsch KW, Su XZ, Wootton JC, Roepe PD, Wellems TE
JournalMol Cell
Volume6
Issue4
Pagination861-71
Date Published2000 Oct
ISSN1097-2765
KeywordsAmino Acid Sequence, Animals, Animals, Genetically Modified, Chloroquine, Digestive System, Drug Resistance, Exons, Humans, Membrane Proteins, Membrane Transport Proteins, Molecular Sequence Data, Mutagenesis, Site-Directed, Plasmodium falciparum, Polymerase Chain Reaction, Protozoan Proteins, Recombinant Proteins, Tetrahydrofolate Dehydrogenase, Transfection, Vacuoles, Verapamil
Abstract

The determinant of verapamil-reversible chloroquine resistance (CQR) in a Plasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7. This segment harbors a 13-exon gene, pfcrt, having point mutations that associate completely with CQR in parasite lines from Asia, Africa, and South America. These data, transfection results, and selection of a CQR line harboring a novel K761 mutation point to a central role for the PfCRT protein in CQR. This transmembrane protein localizes to the parasite digestive vacuole (DV), the site of CQ action, where increased compartment acidification associates with PfCRT point mutations. Mutations in PfCRT may result in altered chloroquine flux or reduced drug binding to hematin through an effect on DV pH.

DOI10.1016/s1097-2765(05)00077-8
Alternate JournalMol Cell
PubMed ID11090624
PubMed Central IDPMC2944663
Grant ListR01 AI050234 / AI / NIAID NIH HHS / United States
R01 AI050234-01 / AI / NIAID NIH HHS / United States
R37 AI050234 / AI / NIAID NIH HHS / United States

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