Plasmodium myosin A drives parasite invasion by an atypical force generating mechanism.
Plasmodium myosin A drives parasite invasion by an atypical force generating mechanism.
复制标题
疟原虫肌球蛋白 A 通过非典型的力产生机制驱动寄生虫入侵。
DOI：
10.1038/s41467-019-11120-0
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发表时间：
2019
影响因子：
16.6
通讯作者：
Houdusse,Anne
中科院分区：
文献类型：
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作者：
Robert-Paganin,Julien;Robblee,JamesP;Auguin,Daniel;Blake,ThomasCA;Bookwalter,CarolS;Krementsova,ElenaB;Moussaoui,Dihia;Previs,MichaelJ;Jousset,Guillaume;Baum,Jake;Trybus,KathleenM;Houdusse,Anne
疟原虫是专性细胞内原生动物和疟疾的病原体，每年造成50万人死亡。寄生虫的生命周期进展依赖于细胞运动，这是一个由肌球蛋白A驱动的过程，肌球蛋白A是一种非传统的单头XIV类分子马达。在这里，我们证明，肌球蛋白A从恶性疟原虫（PfMyoA）是至关重要的红细胞入侵。此外，使用X-射线晶体学，动力学和体外运动分析的组合，我们阐明了非典型的相互作用，驱动这个电机的功能。我们发现，PfMyoA电机性能的重链磷酸化（Ser 19），与未磷酸化的PfMyoA表现出增强的合奏力产生的速度为代价进行调整。因此，调节磷酸化可以优化PfMyoA，用于在寄生虫入侵期间增强力的产生或在传播期间快速运动。本文提出的三种PfMyoA晶体结构为发现旨在预防寄生虫感染的特异性抑制剂提供了蓝图。
Plasmodiumparasites are obligate intracellular protozoa and causative agents of malaria, responsible for half a million deaths each year. The lifecycle progression of the parasite is reliant on cell motility, a process driven by myosin A, an unconventional single-headed class XIV molecular motor. Here we demonstrate that myosin A fromPlasmodium falciparum(PfMyoA) is critical for red blood cell invasion. Further, using a combination of X-ray crystallography, kinetics, and in vitro motility assays, we elucidate the non-canonical interactions that drive this motor’s function. We show that PfMyoA motor properties are tuned by heavy chain phosphorylation (Ser19), with unphosphorylated PfMyoA exhibiting enhanced ensemble force generation at the expense of speed. Regulated phosphorylation may therefore optimize PfMyoA for enhanced force generation during parasite invasion or for fast motility during dissemination. The three PfMyoA crystallographic structures presented here provide a blueprint for discovery of specific inhibitors designed to prevent parasite infection.