小柯机器人

近日，英国牛津大学Matthew K. Higgins及其课题组发现，PfRCR复合物是疟原虫和红细胞入侵过程中的桥梁用。这一研究成果于2023年12月20日在线发表在国际学术期刊《自然》上。

研究人员通过冷冻电镜测定了包含PfRH5、PfCyRPA和PfRIPR的PfRCR复合物结构。研究人员验证了PfRH5打开来插入膜的假说，而显示了刚性的、二硫键锁定的PfRH5可以介导有效的红细胞侵袭。研究人员通过建模和红细胞结合试验证明，与PfCyRPA结合的抗体可通过立体机制中和入侵。研究人员确定了PfRIPR的结构，表明它由一个有序的多域核心与一个伸长的尾部灵活连接组成。

研究人员还发现，PfRIPR的伸长尾部与寄生虫膜上的PfCSS-PfPTRAMP复合物结合，而PfCSS-PfPTRAMP复合物是生长中和抗体的靶标。因此，一个模块化的PfRIPR通过拉长的尾部与裂殖子膜相连，其结构核心呈现出PfCyRPA和PfRH5，可与红细胞受体相互作用。这使人们对红细胞侵袭的分子机制有了新的认识，并为合理设计疫苗开辟了新途径。

据悉，疟疾的症状发生在感染的血液阶段，即寄生虫侵入人体红细胞并在其中复制。PfPCRCR复合物包含PfRH5、PfCyRPA、PfRIPR、PfCSS和PfPTRAMP，是最致命的人类疟原虫恶性疟原虫侵入红细胞的必要条件。针对这些保守蛋白的抗体或纳米抗体可以阻止它们的入侵，使它们成为血期疟疾疫苗的主要候选对象。然而，人们对PfPCRCR在入侵过程中的功能知之甚少。

附：英文原文

Title: The PfRCR complex bridges malaria parasite and erythrocyte during invasion

Author: Farrell, Brendan, Alam, Nawsad, Hart, Melissa N., Jamwal, Abhishek, Ragotte, Robert J., Walters-Morgan, Hannah, Draper, Simon J., Knuepfer, Ellen, Higgins, Matthew K.

Issue&Volume: 2023-12-20

Abstract: The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The PfPCRCR complex1, containing PfRH5 (refs. 2,3), PfCyRPA, PfRIPR, PfCSS and PfPTRAMP, is essential for erythrocyte invasion by the deadliest human malaria parasite, Plasmodium falciparum. Invasion can be prevented by antibodies3,4,5,6 or nanobodies1 against each of these conserved proteins, making them the leading blood-stage malaria vaccine candidates. However, little is known about how PfPCRCR functions during invasion. Here we present the structure of the PfRCR complex7,8, containing PfRH5, PfCyRPA and PfRIPR, determined by cryogenic-electron microscopy. We test the hypothesis that PfRH5 opens to insert into the membrane9, instead showing that a rigid, disulfide-locked PfRH5 can mediate efficient erythrocyte invasion. We show, through modelling and an erythrocyte-binding assay, that PfCyRPA-binding antibodies5 neutralize invasion through a steric mechanism. We determine the structure of PfRIPR, showing that it consists of an ordered, multidomain core flexibly linked to an elongated tail. We also show that the elongated tail of PfRIPR, which is the target of growth-neutralizing antibodies6, binds to the PfCSS–PfPTRAMP complex on the parasite membrane. A modular PfRIPR is therefore linked to the merozoite membrane through an elongated tail, and its structured core presents PfCyRPA and PfRH5 to interact with erythrocyte receptors. This provides fresh insight into the molecular mechanism of erythrocyte invasion and opens the way to new approaches in rational vaccine design.

DOI: 10.1038/s41586-023-06856-1

Source: https://www.nature.com/articles/s41586-023-06856-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html