Maturation and substrate processing topography of the Plasmodium falciparum invasion/egress protease plasmepsin X.
Maturation and substrate processing topography of the Plasmodium falciparum invasion/egress protease plasmepsin X.
复制标题
恶性疟原虫侵入/排出蛋白酶plasmepsin X的成熟和底物加工形貌。
DOI：
10.1038/s41467-022-32271-7
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发表时间：
2022-08-04
影响因子：
16.6
通讯作者：
Goldberg, Daniel E.
中科院分区：
文献类型：
--
作者：
Mukherjee, Sumit;Nguyen, Suong;Sharma, Eashan;Goldberg, Daniel E.
疟疾寄生虫疟原虫侵入宿主红细胞，在寄生虫空泡（PV）内繁殖，然后在称为出口的过程中破裂PV和红细胞膜。出口和入侵都由专门的分泌细胞器分泌的效应蛋白控制。天冬氨酸蛋白酶plasmepsin X（PM X）调节许多这些效应物的活性，但目前还不清楚PM X如何访问其位于不同细胞器中的不同底物。PM X还自动处理以生成不同的异构体。这种处理的功能还不清楚。我们已经绘制了自切割位点，并构建了具有切割位点突变的寄生虫。令人惊讶的是，保持全长的四重突变体保留体外活性，被正常贩运，并支持正常的出口，入侵和寄生虫生长。前结构域的N-末端半部分即使在加工后也保持与催化结构域结合，并且是PM X的适当细胞内运输所需的。我们发现，这种酶裂解微线和外切丝底物放电前，而棒状体底物，是依赖于PM X活动后外切丝放电到PV裂解。这些数据让我们深入了解这种不寻常但重要的天冬氨酸蛋白酶的时间，空间和生化控制。疟原虫从宿主红细胞的逃逸是由效应蛋白介导的。天冬氨酸蛋白酶Plasmepsin X（PM X）调节许多这些效应物的活性，是复制所必需的，并且是有前途的药物靶标。在这里，Mukherjee等人绘制了PM X的自切割位点，表明其前结构域的N-末端部分是细胞内运输所需的，并将PM X在微丝、外丝和棒状体细胞器功能中的成熟和亚细胞活性相关联。
The malaria parasite Plasmodium invades a host erythrocyte, multiplies within a parasitophorous vacuole (PV) and then ruptures the PV and erythrocyte membranes in a process known as egress. Both egress and invasion are controlled by effector proteins discharged from specialized secretory organelles. The aspartic protease plasmepsin X (PM X) regulates activity for many of these effectors, but it is unclear how PM X accesses its diverse substrates that reside in different organelles. PM X also autoprocesses to generate different isoforms. The function of this processing is not understood. We have mapped the self-cleavage sites and have constructed parasites with cleavage site mutations. Surprisingly, a quadruple mutant that remains full-length retains in vitro activity, is trafficked normally, and supports normal egress, invasion and parasite growth. The N-terminal half of the prodomain stays bound to the catalytic domain even after processing and is required for proper intracellular trafficking of PM X. We find that this enzyme cleaves microneme and exoneme substrates before discharge, while the rhoptry substrates that are dependent on PM X activity are cleaved after exoneme discharge into the PV. The data give insight into the temporal, spatial and biochemical control of this unusual but important aspartic protease. Egress of Plasmodium from host erythrocytes is mediated by effector proteins. Aspartic protease plasmepsin X (PM X) regulates the activity for many of these effectors, is essential for replication and is a promising drug target. Here, Mukherjee et al. map the self-cleavage sites of PM X, show that the N-terminal part of its prodomain is required for intracellular trafficking and correlate the maturation and subcellular activity of PM X in microneme, exoneme and rhoptry organelle function.
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