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bioRxiv · 10.1101/2020.06.08.121152

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

Lamy, A.·Macarini-Bruzaferro, E.·Peralvarez-Marin, A.·le Maire, M.·Vazquez-Ibar, J. L.
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Abstract

Efficient mechanisms of lipid transport are indispensable for the Plasmodium malaria parasite along the different stages of its intracellular life-cycle. Gene targeting approaches have recently revealed the irreplaceable role of the Plasmodium-encoded type 4 P-type ATPases (P4-ATPases or lipid flippases), ATP2, together with its potential involvement as antimalarial drug target. In eukaryotic membranes, P4-ATPases assure their asymmetric phospholipid distribution by translocating phospholipids from the outer to the inner leaflet. As ATP2 is a yet putative transporter, 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 heterodimerizes with two of the three Plasmodium-encoded Cdc50 proteins: PcCdc50B and PcCdc50A, indispensable partners for most P4-ATPases. Moreover, the purified PcATP2/PcCdc50B complex catalyses ATP hydrolysis in the presence of phospholipids containing either phosphatidylserine, phosphatidylethanolamine or phosphatidylcholine head groups, and that this activity is upregulated by phosphatidylinositol 4-phosphate. Overall, our work provides the first study of the function and quaternary organization of ATP2, a promising antimalarial drug target candidate.

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Lamy, A., Macarini-Bruzaferro, E., Peralvarez-Marin, A., le Maire, M., Vazquez-Ibar, J. L.. 2020-06-09. ATP2, the essential P4-ATPase of malaria parasites, catalyzes lipid-dependent ATP hydrolysis in complex with a Cdc50 β-subunit. https://doi.org/10.1101/2020.06.08.121152

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