Functional complementation of the ste6 gene of Saccharomyces cerevisiae with the pfmdr1 gene of Plasmodium falciparum.
The pfmdr1 gene has been associated with a drug-resistant phenotype in Plasmodium falciparum, and overexpression of pfmdr1 has been associated with mefloquine- and halofantrine-resistant parasites, but little is known about the functional role of pfmdr1 in this process. Here, we demonstrate that the pfmdr1 gene expressed in a heterologous yeast system functions as a transport molecule and complements a mutation in ste6, a gene which encodes a mating pheromone a-factor export molecule. In addition, the pfmdr1 gene containing two mutations which are associated with naturally occurring chloroquine resistance abolishes this mating phenotype, suggesting that these genetic polymorphisms alter this transport function. Our results support the functional role of pfmdr1 as a transport molecule in the mediation of drug resistance and provide an assay system to address the nature of this transport function.
Volkman
S K
SK
Department of Tropical Public Health, Harvard School of Public Health, Boston, MA 02115, USA.
Cowman
A F
AF
Wirth
D F
DF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D015152:Blotting, Northern; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005656:Fungal Proteins / Q000235:genetics; D005800:Genes, Fungal / Q000235:genetics; D017125:Genes, Protozoan / Q000235:genetics; D005816:Genetic Complementation Test; D006023:Glycoproteins; D000072235:Mating Factor; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000032:analysis / Q000235:genetics; D010641:Phenotype; D010675:Pheromones / Q000032:analysis / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*; D012098:Reproduction; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D017421:Sequence Analysis; D017386:Sequence Homology, Amino Acid
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D005656:Fungal Proteins; D006023:Glycoproteins; D010455:Peptides; D010675:Pheromones; D015800:Protozoan Proteins; C489277:STE6 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000072235:Mating Factor; D002738:Chloroquine