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ATP2, The essential P4-ATPase of malaria parasites, catalyzes lipid-stimulated ATP hydrolysis in complex with a Cdc50 β-subunit

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  • Anaïs Lamy, Universite Paris-Saclay, Umeå University
  • ,
  • Ewerton Macarini-Bruzaferro, Universite Paris-Saclay, Universidade de Sao Paulo
  • ,
  • Thibaud Dieudonné
  • Alex Perálvarez-Marín, Autonomous University of Barcelona
  • ,
  • Guillaume Lenoir, Universite Paris-Saclay
  • ,
  • Cédric Montigny, Universite Paris-Saclay
  • ,
  • Marc le Maire, Universite Paris-Saclay
  • ,
  • José Luis Vázquez-Ibar, Universite Paris-Saclay

Gene targeting approaches have demonstrated the essential role for the malaria parasite of membrane transport proteins involved in lipid transport and in the maintenance of membrane lipid asymmetry, representing emerging oportunites for therapeutical intervention. This is the case of ATP2, a Plasmodium-encoded 4 P-type ATPase (P4-ATPase or lipid flippase), whose activity is completely irreplaceable during the asexual stages of the parasite. Moreover, a recent chemogenomic study has situated ATP2 as the possible target of two antimalarial drug candidates. In eukaryotes, P4-ATPases assure the asymmetric phospholipid distribution in membranes by translocating phospholipids from the outer to the inner leaflet. In this work, we have used a recombinantly-produced P. chabaudi ATP2 (PcATP2), to gain insights into the function and structural organization of this essential transporter. Our work demonstrates that PcATP2 associates with two of the three Plasmodium-encoded Cdc50 proteins: PcCdc50B and PcCdc50A. Purified PcATP2/PcCdc50B complex displays ATPase activity in the presence of either phosphatidylserine or phosphatidylethanolamine. In addition, this activity is upregulated by phosphatidylinositol 4-phosphate. Overall, our work describes the first biochemical characterization of a Plasmodium lipid flippase, a first step towards the understanding of the essential physiological role of this transporter and towards its validation as a potential antimalarial drug target.

Original languageEnglish
JournalEmerging Microbes and Infections
Volume10
Issue1
Pages (from-to)132-147
Number of pages16
DOIs
Publication statusPublished - Jan 2021

    Research areas

  • heterologous expression, lipid flippase, Malaria, membrane transport proteins, P4-ATPases, PfATP2

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