Characterization of the ATP4 ion pump in Toxoplasma gondii.

The Journal of biological chemistry 2019 Apr 05

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The Plasmodium falciparum ATPase PfATP4 is the target of a diverse range of antimalarial compounds, including the clinical drug candidate cipargamin. PfATP4 was originally annotated as a Ca2+ transporter, but recent evidence suggests that it is a Na+ efflux pump, extruding Na+ in exchange for H+ Here we demonstrate that ATP4 proteins belong to a clade of P-type ATPases that are restricted to apicomplexans and their closest relatives. We employed a variety of genetic and physiological approaches to investigate the ATP4 protein of the apicomplexan Toxoplasma gondii, TgATP4. We show that TgATP4 is a plasma membrane protein. Knockdown of TgATP4 had no effect on resting pH or Ca2+ but rendered parasites unable to regulate their cytosolic Na+ concentration ([Na+]cyt). PfATP4 inhibitors caused an increase in [Na+]cyt and a cytosolic alkalinization in WT but not TgATP4 knockdown parasites. Parasites in which TgATP4 was knocked down or disrupted exhibited a growth defect, attributable to reduced viability of extracellular parasites. Parasites in which TgATP4 had been disrupted showed reduced virulence in mice. These results provide evidence for ATP4 proteins playing a key conserved role in Na+ regulation in apicomplexan parasites. © 2019 Lehane et al.

Citation

Adele M Lehane, Adelaide S M Dennis, Katherine O Bray, Dongdi Li, Esther Rajendran, James M McCoy, Hillary M McArthur, Markus Winterberg, Farid Rahimi, Christopher J Tonkin, Kiaran Kirk, Giel G van Dooren. Characterization of the ATP4 ion pump in Toxoplasma gondii. The Journal of biological chemistry. 2019 Apr 05;294(14):5720-5734