Structural, Functional and Computational Studies of Membrane Recognition by Plasmodium Perforin-Like Proteins 1 and 2

Perforin-like proteins (PLPs) play key roles in mechanisms associated with parasitic disease caused by the apicomplexan parasites Plasmodium and Toxoplasma. The T. gondii PLP1 (TgPLP1) mediates tachyzoite egress from cells, while the five Plasmodium PLPs carry out various roles in the life cycle of the parasite and with respect to the molecular basis of disease. Here we focus on Plasmodium vivax PLP1 and PLP2 (PvPLP1 and PvPLP2) compared to TgPLP1. Determination of the crystal structure of the membrane-binding APCI3 domain of PvPLP1 reveals notable differences with TgPLP1, reflected in its inability to bind lipid bilayers as TgPLP1 and PvPLP2 do. Molecular dynamics simulations combined with site-directed mutagenesis and functional assays allow dissection of the binding interactions of TgPLP1 and PvPLP2 on lipid bilayers, and reveal similar tropisms for lipids enriched in the inner leaflet of the mammalian plasma membrane. In addition PvPLP2 displays a secondary synergistic interaction side-on from its principal bilayer interface. This study underlines the substantial differences between the biophysical properties of the APCI3 domains of apicomplexan PLPs, which reflect their significant sequence diversity. Such differences will be important factors in determining the cell targeting and membrane-binding activity of the different proteins in parasitic life cycles and disease.(c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license

Automated summary

Perforin-like proteins (PLPs) play important roles in mechanisms related to parasitic diseases caused by apicomplexan parasites. This study focuses on the comparison of Plasmodium vivax PLP1 and PLP2 with T. gondii PLP1, revealing significant differences in their binding interactions with lipid bilayers. The study highlights the substantial diversity in the biophysical properties of APCI3 domains of apicomplexan PLPs, which have implications for their cell targeting and membrane-binding activities in parasitic life cycles and diseases.