Structural, Functional and Computational Studies of Membrane Recognition by Plasmodium Perforin-Like Proteins 1 and 2.
Structural, Functional and Computational Studies of Membrane Recognition by Plasmodium Perforin-Like Proteins 1 and 2.
复制标题
疟原虫穿孔素样蛋白 1 和 2 膜识别的结构、功能和计算研究。
DOI：
10.1016/j.jmb.2022.167642
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
Williams SI
中科院分区：
文献类型：
--
作者：
Williams SI
穿孔素样蛋白（PLPs）在由顶复门寄生虫（疟原虫和弓形虫）引起的寄生虫病相关机制中起关键作用。T。gondiiPLP1（TgPLP1）介导速殖子从细胞中排出，而五种疟原虫PLPs在寄生虫的生命周期中以及在疾病的分子基础方面发挥各种作用。在这里，我们重点对间日疟原虫PLP1和PLP2（PvPLP1和PvPLP2）相比，TgPLP1。PvPLP 1的膜结合APCβ结构域的晶体结构测定揭示了与TgPLP 1的显着差异，反映在其无法像TgPLP 1和PvPLP 2那样结合脂质双层。分子动力学模拟结合定点诱变和功能测定允许解剖TgPLP1和PvPLP2对脂质双层的结合相互作用，并揭示了类似的向性的脂质丰富的内小叶的哺乳动物质膜。此外，PvPLP2从其主要双层界面侧显示次级协同相互作用。这项研究强调了顶复门PLPs的APCβ结构域的生物物理特性之间的实质性差异，这反映了它们显著的序列多样性。这种差异将是决定寄生虫生命周期和疾病中不同蛋白质的细胞靶向和膜结合活性的重要因素。
Perforin-like proteins (PLPs) play key roles in mechanisms associated with parasitic disease caused by the apicomplexan parasitesPlasmodiumandToxoplasma. TheT. gondiiPLP1 (TgPLP1) mediates tachyzoite egress from cells, while the fivePlasmodiumPLPs carry out various roles in the life cycle of the parasite and with respect to the molecular basis of disease. Here we focus onPlasmodium vivaxPLP1 and PLP2 (PvPLP1 and PvPLP2) compared to TgPLP1. Determination of the crystal structure of the membrane-binding APCβ 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 APCβ 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.