Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies.
Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies.
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DOI：
10.1038/nature13715
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发表时间：
2014-11-20
期刊：
影响因子：
64.8
通讯作者：
Higgins, Matthew K.
中科院分区：
文献类型：
--
作者：
Wright, Katherine E.;Hjerrild, Kathryn A.;Bartlett, Jonathan;Douglas, Alexander D.;Jin, Jing;Brown, Rebecca E.;Illingworth, Joseph J.;Ashfield, Rebecca;Clemmensen, Stine B.;de Jongh, Willem A.;Draper, Simon J.;Higgins, Matthew K.
侵入宿主红细胞是疟原虫生命周期和疟疾病理发展的关键。红细胞侵入的阶段，包括初始接触、顶端重定向、连接形成和主动内陷，由专门的顶端细胞器及其寄生虫蛋白质内容物的协调释放指导。在这些蛋白质中，所有物种入侵的中心，是两个寄生虫蛋白家族，网织红细胞结合蛋白同源物（RH）和红细胞结合样蛋白，介导宿主-寄生虫相互作用。来自恶性疟原虫的RH 5（PfRH 5）是任一家族的唯一成员，其通过与红细胞表面蛋白basigin（也称为CD 147和EMMPRIN）的相互作用被证明是所有测试菌株中红细胞侵入所必需的。靶向PfRH 5或basigin的抗体在体外有效阻断寄生虫入侵，使PfRH 5成为一种优秀的候选疫苗。在这里，我们提出了晶体结构的PfRH 5与basigin和两个不同的抑制性抗体的复合物。PfRH 5采用了一种新的折叠，其中两个三螺旋束在风筝状结构中聚集在一起，在一个尖端呈现basigin和抑制性抗体的结合位点。这提供了第一个结构洞察红细胞结合thepasmodiumRH蛋白家族，并确定新的抑制性表位，以指导设计新一代的疫苗，对血液阶段的寄生虫。
Invasion of host erythrocytes is essential to the life cycle ofPlasmodiumparasites and development of the pathology of malaria. The stages of erythrocyte invasion, including initial contact, apical reorientation, junction formation, and active invagination, are directed by coordinated release of specialized apical organelles and their parasite protein contents. Among these proteins, and central to invasion by all species, are two parasite protein families, the reticulocyte-binding protein homologue (RH) and erythrocyte-binding like proteins, which mediate host–parasite interactions. RH5 fromPlasmodium falciparum(PfRH5) is the only member of either family demonstrated to be necessary for erythrocyte invasion in all tested strains, through its interaction with the erythrocyte surface protein basigin (also known as CD147 and EMMPRIN),. Antibodies targeting PfRH5 or basigin efficiently block parasite invasionin vitro,,,,,, making PfRH5 an excellent vaccine candidate. Here we present crystal structures of PfRH5 in complex with basigin and two distinct inhibitory antibodies. PfRH5 adopts a novel fold in which two three-helical bundles come together in a kite-like architecture, presenting binding sites for basigin and inhibitory antibodies at one tip. This provides the first structural insight into erythrocyte binding by thePlasmodiumRH protein family and identifies novel inhibitory epitopes to guide design of a new generation of vaccines against the blood-stage parasite.
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