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Mutations in transmembrane domains 1, 4 and 9 of the Plasmodium falciparum chloroquine resistance transporter alter susceptibility to chloroquine, quinine and quinidine
Molecular Microbiology (2007)
  • Roland A. Cooper, Department of Biological Sciences, Old Dominion University
  • Kristin D. Lane, Department of Biological Sciences, Old DominionUniversity
  • Bingbing Deng, Department of Biological Sciences, University of NotreDame
  • Jianbing Mu, Laboratory of Malaria and Vector Research, NationalInstitute of Allergy and Infectious Diseases
  • Jigar J. Patel, Department of Biological Sciences, University of NotreDame
  • Thomas E. Wellems, Laboratory of Malaria and Vector Research, NationalInstitute of Allergy and Infectious Diseases
  • Xin-zhuan Su, Laboratory of Malaria and Vector Research, NationalInstitute of Allergy and Infectious Diseases
  • Michael T. Ferdig, Department of Biological Sciences, University of NotreDame
Abstract
Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT) can result in verapamil-reversible CQ resistance and altered susceptibility to other antimalarials. PfCRT contains 10 membrane-spanning domains and is found in the digestive vacuole (DV) membrane of intraerythrocytic parasites. The mechanism by which PfCRT mediates CQ resistance is unclear although it is associated with decreased accumulation of drug within the DV. On the permissive background of the P. falciparum 106/1(K76) parasite line, we used single-step drug selection to generate isogenic clones containing unique pfcrt point mutations that resulted in amino acid changes in PfCRT transmembrane domains 1 (C72R, K76N, K76I and K76T) and 9 (Q352K, Q352R). The resulting changes of charge and hydropathy affected quantitative CQ susceptibility and accumulation as well as the stereospecific responses to quinine and quinidine. These results, together with a previously described S163R mutation in transmembrane domain 4, indicate that transmembrane segments 1, 4 and 9 of PfCRT provide important structural components of a substrate recognition and translocation domain. Charge-affecting mutations within these segments may affect the ability of PfCRT to bind different quinoline drugs and determine their net accumulation in the DV.
Disciplines
Publication Date
January, 2007
Citation Information
Roland A. Cooper, Kristin D. Lane, Bingbing Deng, Jianbing Mu, et al.. "Mutations in transmembrane domains 1, 4 and 9 of the Plasmodium falciparum chloroquine resistance transporter alter susceptibility to chloroquine, quinine and quinidine" Molecular Microbiology Vol. 63 Iss. 1 (2007) p. 270 - 282 ISSN: 1365-2958
Available at: http://works.bepress.com/roland_cooper/21/