title: Malaria parasite clag3 genes determine channel-mediated nutrient uptake by infected red blood cells.
abstract: Development of malaria parasites within vertebrate erythrocytes requires nutrient uptake at the host cell membrane. The plasmodial surface anion channel (PSAC) mediates this transport and is an antimalarial target, but its molecular basis is unknown. We report a parasite gene family responsible for PSAC activity. We used high-throughput screening for nutrient uptake inhibitors to identify a compound highly specific for channels from the Dd2 line of the human pathogen P. falciparum. Inheritance of this compound's affinity in a Dd2 × HB3 genetic cross maps to a single parasite locus on chromosome 3. DNA transfection and in vitro selections indicate that PSAC-inhibitor interactions are encoded by two clag3 genes previously assumed to function in cytoadherence. These genes are conserved in plasmodia, exhibit expression switching, and encode an integral protein on the host membrane, as predicted by functional studies. This protein increases host cell permeability to diverse solutes.
authors.affiliation: The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Wang
authors.initials: W
authors.lastname: Nguitragool
authors.forename: Abdullah A B
authors.initials: AA
authors.lastname: Bokhari
authors.forename: Ajay D
authors.initials: AD
authors.lastname: Pillai
authors.forename: Kempaiah
authors.initials: K
authors.lastname: Rayavara
authors.forename: Paresh
authors.initials: P
authors.lastname: Sharma
authors.forename: Brad
authors.initials: B
authors.lastname: Turpin
authors.forename: L
authors.initials: L
authors.lastname: Aravind
authors.forename: Sanjay A
authors.initials: SA
authors.lastname: Desai
mesh_terms: D000595:Amino Acid Sequence; D003433:Crosses, Genetic; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology*; D057166:High-Throughput Screening Assays; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D007976:Leupeptins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010539:Permeability; D010963:Plasmodium falciparum / Q000235:genetics* / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D007473:Ion Channels; D007976:Leupeptins; D015800:Protozoan Proteins; C502072:cytoadherence-linked asexual protein 3, Plasmodium falciparum; C505335:surface anion channel protein, Plasmodium falciparum; C032854:leupeptin