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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 wild type, but not in TgATP4-knockdown, parasites.  Parasites in which TgATP4 was knocked down or disrupted exhibited a growth defect, attributable to a 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.

Original publication

DOI

10.1074/jbc.ra118.006706

Type

Journal article

Journal

The Journal of biological chemistry

Publication Date

05/02/2019

Addresses

Research School of Biology, Australian National University, Australia.