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Cryo-EM structure of an essential Plasmodium vivax invasion complex

机译：必要的间日疟原虫入侵复合体的Cryo-EM结构。

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摘要

Plasmodium vivax is the most widely distributed malaria parasite that infects humans(1). P. vivax invades reticulocytes exclusively, and successful entry depends on specific interactions between the P. vivax reticulocyte-binding protein 2b (PvRBP2b) and transferrin receptor 1 (TfR1)(2). TfR1-deficient erythroid cells are refractory to invasion by P. vivax, and anti-PvRBP2b monoclonal antibodies inhibit reticulocyte binding and block P. vivax invasion in field isolates(2). Here we report a high-resolution cryo-electron microscopy structure of a ternary complex of PvRBP2b bound to human TfR1 and transferrin, at 3.7 angstrom resolution. Mutational analyses show that PvRBP2b residues involved in complex formation are conserved; this suggests that antigens could be designed that act across P. vivax strains. Functional analyses of TfR1 highlight how P. vivax hijacks TfR1, an essential housekeeping protein, by binding to sites that govern host specificity, without affecting its cellular function of transporting iron. Crystal and solution structures of PvRBP2b in complex with antibody fragments characterize the inhibitory epitopes. Our results establish a structural framework for understanding how P. vivax reticulocyte-binding protein engages its receptor and the molecular mechanism of inhibitory monoclonal antibodies, providing important information for the design of novel vaccine candidates.
机译：间日疟原虫是感染人类的​​分布最广泛的疟原虫（1）。间日疟原虫仅侵袭网状细胞，成功进入取决于间日疟原虫网状细胞结合蛋白2b（PvRBP2b）和转铁蛋白受体1（TfR1）（2）之间的特异性相互作用。缺乏TfR1的红系细胞难以抵御间日疟原虫的侵袭，抗PvRBP2b单克隆抗体抑制网状细胞的结合并阻断田间分离株对间日疟原虫的侵袭（2）。在这里，我们报告高分辨率的低温电子显微镜结构的PvRBP2b三元复合物绑定到人类TfR1和转铁蛋白，在3.7埃分辨率。突变分析表明，参与复合物形成的PvRBP2b残基是保守的。这表明可以设计跨间日疟原虫菌株起作用的抗原。 TfR1的功能分析突出了间日疟原虫如何通过与控制宿主特异性的位点结合而劫持TfR1（一种基本的管家蛋白），而不影响其转运铁的细胞功能。与抗体片段复合的PvRBP2b的晶体和溶液结构表征了抑制性表位。我们的研究结果为了解间日疟原虫网织红细胞结合蛋白如何与受体结合以及抑制性单克隆抗体的分子机制建立了结构框架，为新型疫苗的设计提供了重要信息。

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  • 来源
    《Nature》 |2018年第7712期|135-139|共5页
  • 作者

    Gruszczyk Jakub; Huang Rick K.; Chan Li-Jin; Menant Sebastien; Hong Chuan; Murphy James M.; Mok Yee-Foong; Griffin Michael D. W.; Pearson Richard D.; Wong Wilson; Cowman Alan F.; Yu Zhiheng; Wai-Hong Tham;

  • 作者单位

    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia;

    Howard Hughes Med Inst, CryoEM Shared Resource, Janelia Res Campus, Ashburn, VA 20147 USA;

    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia;

    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia;

    Howard Hughes Med Inst, CryoEM Shared Resource, Janelia Res Campus, Ashburn, VA 20147 USA;

    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia;

    Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Dept Biochem & Mol Biol, Melbourne, Vic, Australia;

    Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Dept Biochem & Mol Biol, Melbourne, Vic, Australia;

    Wellcome Trust Sanger Inst, Cambridge, England;

    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia;

    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia;

    Howard Hughes Med Inst, CryoEM Shared Resource, Janelia Res Campus, Ashburn, VA 20147 USA;

    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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