Activation of the Plasmodium Egress Effector Subtilisin-Like Protease 1 Is Mediated by Plasmepsin X Destruction of the Prodomain.
Activation of the Plasmodium Egress Effector Subtilisin-Like Protease 1 Is Mediated by Plasmepsin X Destruction of the Prodomain.
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DOI：
10.1128/mbio.00673-23
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发表时间：
2023-04-25
期刊：
影响因子：
6.4
通讯作者：
Goldberg, Daniel E.
中科院分区：
文献类型：
--
作者：
Mukherjee, Sumit;Nasamu, Armiyaw S.;Rubiano, Kelly C.;Goldberg, Daniel E.
在每一轮复制之后，疟原虫恶性疟原虫的子代子体通过破坏寄生液泡膜（PVM）和红细胞膜（RBCM）从被感染的宿主红细胞（RBC）中逃脱（出口）。由寄生虫丝氨酸蛋白酶，枯草杆菌样蛋白酶1 （SUB1）策划的蛋白水解级联调节膜的破坏。SUB1激活涉及将82-kDa的酶原初步自动加工成54-kDa （p54）中间体，该中间体在切割后仍与抑制原体（p31）结合。第二处理步骤将p54转换为终端47-kDa （p47）形式的SUB1。尽管天冬氨酸蛋白酶plasmepsin X （PM X）与SUB1的激活有关，但其机制尚不清楚。在这里，我们发现在敲除PM X后，SUB1的抑制p31-p54复合物在寄生虫中积累。利用重组PM X和SUB1，我们发现PM X可以直接切割p31和p54。我们绘制了重组p31上的裂解位点。此外，我们证明p54到p47的转化可以受到相邻的SUB1或PM X切割位点的切割影响。重要的是，一旦p31被移除，p54在寄生虫体内完全发挥功能，这表明向p47的转化对于SUB1的活性是必不可少的。通过异源蛋白酶解除propiece抑制是一种新的枯草菌素激活机制。
Following each round of replication, daughter merozoites of the malaria parasite Plasmodium falciparum escape (egress) from the infected host red blood cell (RBC) by rupturing the parasitophorous vacuole membrane (PVM) and the RBC membrane (RBCM). A proteolytic cascade orchestrated by a parasite serine protease, subtilisin-like protease 1 (SUB1), regulates the membrane breakdown. SUB1 activation involves primary autoprocessing of the 82-kDa zymogen to a 54-kDa (p54) intermediate that remains bound to its inhibitory propiece (p31) postcleavage. A second processing step converts p54 to the terminal 47-kDa (p47) form of SUB1. Although the aspartic protease plasmepsin X (PM X) has been implicated in the activation of SUB1, the mechanism remains unknown. Here, we show that upon knockdown of PM X, the inhibitory p31-p54 complex of SUB1 accumulates in the parasites. Using recombinant PM X and SUB1, we show that PM X can directly cleave both p31 and p54. We have mapped the cleavage sites on recombinant p31. Furthermore, we demonstrate that the conversion of p54 to p47 can be effected by cleavage at either SUB1 or PM X cleavage sites that are adjacent to one another. Importantly, once the p31 is removed, p54 is fully functional inside the parasites, suggesting that the conversion to p47 is dispensable for SUB1 activity. Relief of propiece inhibition via a heterologous protease is a novel mechanism for subtilisin activation.
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加工恶性疟原虫梅罗唑群体表面蛋白MSP1激活谱线结合功能，从而使RBC的寄生虫出口。
影响因子：
30.3
作者：
Das S;Hertrich N;Perrin AJ;Withers-Martinez C;Collins CR;Jones ML;Watermeyer JM;Fobes ET;Martin SR;Saibil HR;Wright GJ;Treeck M;Epp C;Blackman MJ
通讯作者：
Blackman MJ
影响因子：
6.7
作者：
Collins CR;Hackett F;Strath M;Penzo M;Withers-Martinez C;Baker DA;Blackman MJ
通讯作者：
Blackman MJ
影响因子：
7.8
作者：
Klemba, M;Beatty, W;Goldberg, DE
通讯作者：
Goldberg, DE
DOI：
10.1073/pnas.83.10.3096
发表时间：
1986-05-01
影响因子：
11.1
作者：
POWER, SD;ADAMS, RM;WELLS, JA
通讯作者：
WELLS, JA
影响因子：
16.6
作者：
Mukherjee, Sumit;Nguyen, Suong;Sharma, Eashan;Goldberg, Daniel E.
通讯作者：
Goldberg, Daniel E.