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J Biol Chem. 2019 Feb 5. pii: jbc.RA118.006706. doi: 10.1074/jbc.RA118.006706. [Epub ahead of print]

Characterization of the ATP4 ion pump in Toxoplasma gondii.

Author information

1
Research School of Biology, Australian National University, Australia.
2
Australian National University, Australia.
3
The Walter and Eliza Hall Institute.
4
Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Australia.
5
The Research School of Biology, The Australian National University, Australia.

Abstract

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.

KEYWORDS:

ATPase; Na+ pump; TgATP4; Toxoplasma gondii; cipargamin; drug action; malaria; membrane transport; protozoan parasite; sodium transporter

PMID:
30723156
DOI:
10.1074/jbc.RA118.006706
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