Molecular identification of a malaria merozoite surface sheddase.
Molecular identification of a malaria merozoite surface sheddase.
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DOI：
10.1371/journal.ppat.0010029
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发表时间：
2005-11
期刊：
影响因子：
6.7
通讯作者：
Blackman MJ
中科院分区：
文献类型：
--
作者：
Harris PK;Yeoh S;Dluzewski AR;O'Donnell RA;Withers-Martinez C;Hackett F;Bannister LH;Mitchell GH;Blackman MJ
顶复门寄生虫入侵过程中表面蛋白的蛋白水解脱落是一种普遍现象，被认为是寄生虫脱离粘附素-受体复合物以进入宿主细胞的一种机制。恶性疟原虫裂殖子侵入红细胞需要脱落两种基本表面蛋白质的胞外域成分，称为MSP 1和AMA 1。两者都是由相同的裂殖子表面“脱落酶”释放的，但这种蛋白酶的分子身份和作用方式尚不清楚。在这里，我们将其鉴定为PfSUB 2，一种整合的膜枯草杆菌蛋白酶样蛋白酶（枯草杆菌酶）。我们发现，PfSUB 2存储在顶端分泌细胞器称为微线。在裂殖子释放后，它被分泌到寄生虫表面，并以肌动蛋白依赖的方式易位到其后极，预测的脱落酶的运输模式。枯草杆菌酶前肽通常是其同源蛋白酶的选择性抑制剂，PfSUB 2前肽也不例外;我们表明重组PfSUB 2前肽特异性结合成熟寄生虫衍生的PfSUB 2，是MSP 1和AMA 1脱落的有效选择性抑制剂，直接建立PfSUB 2作为脱落酶。PfSUB 2是一种新的潜在药物靶点，旨在防止疟疾寄生虫侵入红细胞。疟疾在地球仪各地造成巨大痛苦和生命损失。面对对现有药物日益增长的耐药性和没有获得许可的疫苗，迫切需要新的方法来解决其控制问题。其中最重要的是提高对疟原虫基本生物学的认识。寄生虫侵入并在红细胞内复制。在入侵过程中，许多重要的蛋白质需要从寄生虫表面脱落，可能是为了脱离使初始结合成为可能的粘附相互作用。这些表面蛋白的脱落是由一种叫做蛋白酶的寄生虫酶实现的，阻断这种蛋白酶作用的化合物或抗体可以阻止入侵，杀死寄生虫。在这里，作者将这种蛋白酶鉴定为PfSUB 2，它是枯草杆菌蛋白酶样蛋白酶超家族的一个大的膜结合成员。他们发现PfSUB 2在入侵点从称为微丝的顶端细胞器中分泌出来，在寄生虫的表面上向后迁移，并且被设计为PfSUB 2的特异性抑制剂的蛋白质可以有效地防止寄生虫表面蛋白的脱落。这项工作为开发PfSUB 2抑制剂作为新一代抗疟药物奠定了基础。
Proteolytic shedding of surface proteins during invasion by apicomplexan parasites is a widespread phenomenon, thought to represent a mechanism by which the parasites disengage adhesin-receptor complexes in order to gain entry into their host cell. Erythrocyte invasion by merozoites of the malaria parasite Plasmodium falciparum requires the shedding of ectodomain components of two essential surface proteins, called MSP1 and AMA1. Both are released by the same merozoite surface “sheddase,” but the molecular identity and mode of action of this protease is unknown. Here we identify it as PfSUB2, an integral membrane subtilisin-like protease (subtilase). We show that PfSUB2 is stored in apical secretory organelles called micronemes. Upon merozoite release it is secreted onto the parasite surface and translocates to its posterior pole in an actin-dependent manner, a trafficking pattern predicted of the sheddase. Subtilase propeptides are usually selective inhibitors of their cognate protease, and the PfSUB2 propeptide is no exception; we show that recombinant PfSUB2 propeptide binds specifically to mature parasite-derived PfSUB2 and is a potent, selective inhibitor of MSP1 and AMA1 shedding, directly establishing PfSUB2 as the sheddase. PfSUB2 is a new potential target for drugs designed to prevent erythrocyte invasion by the malaria parasite. Malaria causes immense suffering and loss of life across the globe. In the face of growing resistance to available drugs and no licensed vaccine, new approaches are urgently required to tackle its control. Fundamental to these is an improved understanding of the basic biology of the malaria parasite. The parasite invades and replicates within red blood cells. During invasion a number of important proteins need to be shed from the parasite surface, probably in order to disengage the adhesive interactions that enable initial binding. Shedding of these surface proteins is achieved by a parasite enzyme called a protease, and compounds or antibodies that block the action of this protease prevent invasion, killing the parasite. Here the authors identify this protease as PfSUB2, a large, membrane-bound member of the subtilisin-like protease superfamily. They find that PfSUB2 is secreted from apical organelles called micronemes at the point of invasion to migrate rearwards over the surface of the parasite, and that a protein designed to be a specific inhibitor of PfSUB2 potently prevents shedding of parasite surface proteins. This work sets the scene for the development of inhibitors of PfSUB2 as a new generation of antimalarial drugs.
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影响因子：
4.8
作者：
Fleck, SL;Birdsall, B;Holder, AA
通讯作者：
Holder, AA
影响因子：
3.1
作者：
Gantt, S;Persson, C;Nussenzweig, V
通讯作者：
Nussenzweig, V
影响因子：
3.5
作者：
Craven, RA;Griffiths, DJF;Carr, AM
通讯作者：
Carr, AM
DOI：
10.1084/jem.172.1.379
发表时间：
1990-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Blackman MJ;Heidrich HG;Donachie S;McBride JS;Holder AA
通讯作者：
Holder AA
影响因子：
4.8
作者：
Fugère, M;Limperis, PC;Day, R
通讯作者：
Day, R