Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA

  1. Lin Chen
  2. Yibin Xu
  3. Wilson Wong
  4. Jennifer K Thompson
  5. Julie Healer
  6. Ethan Goddard-Borger
  7. Michael C Lawrence
  8. Alan F Cowman  Is a corresponding author
  1. The Walter and Eliza Hall Institute of Medical Research, Australia

Abstract

Plasmodium falciparum causes malaria in humans with over 450,000 deaths annually. The asexual blood stage involves invasion of erythrocytes by merozoites, in which they grow and divide to release daughter merozoites, which in turn invade new erythrocytes perpetuating the cycle responsible for malaria. A key step in merozoite invasion is the essential binding of PfRh5/CyRPA/PfRipr complex to basigin, a step linked to formation of a pore between merozoites and erythrocytes. We show CyRPA interacts directly with PfRh5. An invasion inhibitory monoclonal antibody to CyRPA blocks binding of CyRPA to PfRh5 and complex formation thus illuminating the molecular mechanism for inhibition of parasite growth. We determined the crystal structures of CyRPA alone and in complex with antibody Fab fragment. CyRPA has a six-bladed β-propeller fold, and we identify the region that interacts with PfRh5. This functionally conserved epitope is a potential target for vaccines against P. falciparum.

Article and author information

Author details

  1. Lin Chen

    The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Yibin Xu

    The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Wilson Wong

    The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Jennifer K Thompson

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Julie Healer

    The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Ethan Goddard-Borger

    The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Michael C Lawrence

    The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Alan F Cowman

    The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    For correspondence
    cowman@wehi.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5145-9004

Funding

Victorian State Government OIS and NHMRC IRIISS

  • Lin Chen
  • Yibin Xu
  • Wilson Wong
  • Jennifer K Thompson
  • Ethan Goddard-Borger
  • Michael C Lawrence
  • Alan F Cowman

Howard Hughes Medical Institute (55007645)

  • Alan F Cowman

National Health and Medical Research Council (637406)

  • Alan F Cowman

Path/Malaria Vaccine Initiative (07608-COL)

  • Alan F Cowman

United States Agency for International Development (07608-COL)

  • Alan F Cowman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Stephen C. Harrison, Harvard Medical School, United States

Publication history

  1. Received: September 12, 2016
  2. Accepted: January 31, 2017
  3. Accepted Manuscript published: February 14, 2017 (version 1)
  4. Version of Record published: March 14, 2017 (version 2)

Copyright

© 2017, Chen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lin Chen
  2. Yibin Xu
  3. Wilson Wong
  4. Jennifer K Thompson
  5. Julie Healer
  6. Ethan Goddard-Borger
  7. Michael C Lawrence
  8. Alan F Cowman
(2017)
Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA
eLife 6:e21347.
https://doi.org/10.7554/eLife.21347

Further reading

    1. Structural Biology and Molecular Biophysics
    2. Microbiology and Infectious Disease
    Paola Favuzza, Elena Guffart ... Markus G Rudolph
    Research Article Updated

    Invasion of erythrocytes by Plasmodial merozoites is a composite process involving the interplay of several proteins. Among them, the Plasmodium falciparum Cysteine-Rich Protective Antigen (PfCyRPA) is a crucial component of a ternary complex, including Reticulocyte binding-like Homologous protein 5 (PfRH5) and the RH5-interacting protein (PfRipr), essential for erythrocyte invasion. Here, we present the crystal structures of PfCyRPA and its complex with the antigen-binding fragment of a parasite growth inhibitory antibody. PfCyRPA adopts a 6-bladed β-propeller structure with similarity to the classic sialidase fold, but it has no sialidase activity and fulfills a purely non-enzymatic function. Characterization of the epitope recognized by protective antibodies may facilitate design of peptidomimetics to focus vaccine responses on protective epitopes. Both in vitro and in vivo anti-PfCyRPA and anti-PfRH5 antibodies showed more potent parasite growth inhibitory activity in combination than on their own, supporting a combined delivery of PfCyRPA and PfRH5 in vaccines.

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