Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance

Authors

David A. Fidock, National Institute of Allergy and Infectious Diseases, National Institutes of HealthFollow
Takashi Nomura, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Angela K. Talley, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Roland A. Cooper, National Institute of Allergy and Infectious Diseases, National Institutes of HealthFollow
Sergey M. Dzekunov, Department of Chemistry, Program in Tumor Biology, Lombardi Cancer Center, Georgetown University
Michael T. Ferdig, National Institute of Allergy and Infectious Diseases, National Institutes of HealthFollow
Lyann M. B. Ursos, Department of Chemistry, Program in Tumor Biology, Lombardi Cancer Center, Georgetown University
Amar bir Singh Sidhu, Department of Microbiology and Immunology, Albert Einstein College of Medicine
Bronwen Naude, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Kirk W. Deitsch, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Xin-zhuan Su, National Institute of Allergy and Infectious Diseases, National Institutes of HealthFollow
John C. Wooten, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Paul D. Roepe, Department of Chemistry, Program in Tumor Biology, Lombardi Cancer Center, Georgetown UniversityFollow
Thomas E. Wellems, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Document Type

Article

Source

Molecular Cell

ISSN

1097-4164

Volume

6

Issue

4

First Page

861

Last Page

871

Publication Date

10-2000

Department

Natural Sciences and Mathematics

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.

Rights

Copyright © 2000 Cell Press. All rights reserved.

PubMed ID

11090624