Cryo-EM structure of an essential Plasmodium vivax invasion complex

Jakub Gruszczyk, Rick K. Huang, Li-Jin Chan, Sébastien Menant, Chuan Hong, James M. Murphy, Yee-Foong Mok, Michael D. W. Griffin, Richard D. Pearson, Wilson Wong, Alan F. Cowman, Zhiheng Yu () and Wai-Hong Tham ()
Additional contact information
Jakub Gruszczyk: The Walter and Eliza Hall Institute of Medical Research
Rick K. Huang: CryoEM Shared Resource, Janelia Research Campus, Howard Hughes Medical Institute
Li-Jin Chan: The Walter and Eliza Hall Institute of Medical Research
Sébastien Menant: The Walter and Eliza Hall Institute of Medical Research
Chuan Hong: CryoEM Shared Resource, Janelia Research Campus, Howard Hughes Medical Institute
James M. Murphy: The Walter and Eliza Hall Institute of Medical Research
Yee-Foong Mok: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
Michael D. W. Griffin: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
Richard D. Pearson: Wellcome Trust Sanger Institute
Wilson Wong: The Walter and Eliza Hall Institute of Medical Research
Alan F. Cowman: The Walter and Eliza Hall Institute of Medical Research
Zhiheng Yu: CryoEM Shared Resource, Janelia Research Campus, Howard Hughes Medical Institute
Wai-Hong Tham: The Walter and Eliza Hall Institute of Medical Research

Nature, 2018, vol. 559, issue 7712, 135-139

Abstract: Abstract Plasmodium vivax is the most widely distributed malaria parasite that infects humans1. 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 isolates2. 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 Å 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.

Date: 2018
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DOI: 10.1038/s41586-018-0249-1

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