Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Mol Microbiol. 2010 Oct;78(1):187-202. doi: 10.1111/j.1365-2958.2010.07324.x. Epub 2010 Feb 8.
The malaria parasite Plasmodium falciparum invades erythrocytes where it replicates to produce invasive merozoites, which eventually egress to repeat the cycle. Merozoite surface protein-1 (MSP1), a prime malaria vaccine candidate and one of the most abundant components of the merozoite surface, is implicated in the ligand-receptor interactions leading to invasion. MSP1 is extensively proteolytically modified, first just before egress and then during invasion. These primary and secondary processing events are mediated respectively, by two parasite subtilisin-like proteases, PfSUB1 and PfSUB2, but the function and biological importance of the processing is unknown. Here, we examine the regulation and significance of MSP1 processing. We show that primary processing is ordered, with the primary processing site closest to the C-terminal end of MSP1 being cleaved last, irrespective of polymorphisms throughout the rest of the molecule. Replacement of the secondary processing site, normally refractory to PfSUB1, with a PfSUB1-sensitive site, is deleterious to parasite growth. Our findings show that correct spatiotemporal regulation of MSP1 maturation is crucial for the function of the protein and for maintenance of the parasite asexual blood-stage life cycle.
疟原虫恶性疟原虫侵入红细胞，在红细胞内繁殖产生入侵的裂殖子，最终逸出以重复循环。裂殖子表面蛋白-1（MSP1）是主要的疟疾疫苗候选物之一，也是裂殖子表面最丰富的成分之一，它参与了导致入侵的配体-受体相互作用。MSP1 广泛地被蛋白水解修饰，首先在逸出之前，然后在入侵期间。这些主要和次要的加工事件分别由两种寄生虫枯草杆菌蛋白酶样蛋白酶 PfSUB1 和 PfSUB2 介导，但加工的功能和生物学重要性尚不清楚。在这里，我们研究了 MSP1 加工的调控和意义。我们表明，初级加工是有序的，与 MSP1 的 C 末端最接近的初级加工位点最后被切割，而与分子其余部分的多态性无关。用 PfSUB1 敏感位点替换通常对 PfSUB1 有抗性的次级加工位点对寄生虫的生长是有害的。我们的发现表明，正确的 MSP1 成熟的时空调控对蛋白质的功能和寄生虫无性血期生命周期的维持至关重要。
