Conference Agenda

Type IV P-type ATPases (P4-ATPases) are critical regulators of membrane lipid asymmetry in eukaryotic cells. Plasmodium falciparum is predicted to encode six P4-ATPases, but their roles remain to be defined. Recently, amplification of the gene encoding one of these, PfATP2, was associated with resistance to the antiplasmodial compounds MMV007224 and MMV665794. Here, we show that PfATP2 is a plasma membrane localised P4-ATPase that functions as a phospholipid flippase and is important for parasite growth. Using genetically modified parasites, we found that the PfATP2 expression level of parasites correlates with the rate by which they internalise a fluorescent analogue of phosphatidylserine (NBD-PS). Overexpression of PfATP2 enhanced NBD-PS translocation, whereas conditional knockdown significantly impaired this process. Further, exposure of parasites to MMV007224 and MMV665794 gave rise to a reduction in NBD-PS internalisation. PfATP2 knockdown parasites were hypersensitive to growth inhibition by MMV007224 and MMV665794, while PfATP2 overexpressing parasites were resistant to the compounds. Taken together, these findings establish PfATP2 as a major contributor to ATP-dependent phosphatidylserine internalisation on the parasite plasma membrane and a potential target of MMV007224 and MMV665794. We are currently investigating whether a reduction in PfATP2-mediated phospholipid flipping affects the activities of other transporters on the parasite plasma membrane.