1. Structural Biology and Molecular Biophysics
  2. Microbiology and Infectious Disease
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Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody

  1. Paola Favuzza
  2. Elena Guffart
  3. Marco Tamborrini
  4. Bianca Scherer
  5. Anita M Dreyer
  6. Arne C Rufer
  7. Johannes Erny
  8. Joerg Hoernschemeyer
  9. Ralf Thoma
  10. Georg Schmid
  11. Bernard Gsell
  12. Araceli Lamelas
  13. Joerg Benz
  14. Catherine Joseph
  15. Hugues Matile
  16. Gerd Pluschke  Is a corresponding author
  17. Markus G Rudolph  Is a corresponding author
  1. Swiss Tropical and Public Health Institute, Switzerland
  2. Roche Innovation Center Basel, Switzerland
  3. Instituto de Ecología A.C., Mexico
Research Article
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Cite this article as: eLife 2017;6:e20383 doi: 10.7554/eLife.20383

Abstract

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 structure of PfCyRPA and of its complex with the antigen-binding fragment of a parasite growth inhibitory antibody. While PfCyRPA adopts a 6-bladed β-propeller structure with similarity to the classic sialidase fold, it possesses no sialidase activity, indicating that it fulfills a non-enzymatic function. Characterization of the epitope recognized by protective antibodies will facilitate design of peptidomimetics that 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.

Article and author information

Author details

  1. Paola Favuzza

    Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1394-927X

  2. Elena Guffart

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  3. Marco Tamborrini

    Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  4. Bianca Scherer

    Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  5. Anita M Dreyer

    Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  6. Arne C Rufer

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  7. Johannes Erny

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  8. Joerg Hoernschemeyer

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  9. Ralf Thoma

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  10. Georg Schmid

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  11. Bernard Gsell

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  12. Araceli Lamelas

    Red de Estudios Moleculares Avanzados, Instituto de Ecología A.C., Xalapa, Mexico
    Competing interests
    The authors declare that no competing interests exist.

  13. Joerg Benz

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  14. Catherine Joseph

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  15. Hugues Matile

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  16. Gerd Pluschke

    Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland
    For correspondence
    Gerd.Pluschke@unibas.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1957-2925

  17. Markus G Rudolph

    Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
    For correspondence
    markus.rudolph@roche.com
    Competing interests
    The authors declare that no competing interests exist.

Funding

Uniscientia Stiftung

  • Gerd Pluschke

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

Ethics

Animal experimentation: All procedures involving living animals were performed in strict accordance with the Rules and Regulations for the Protection of Animal Rights (Tierschutzverordnung) of the Swiss Federal Food Safety and Veterinary Office. The protocol was granted ethical approval by the Veterinary Office of the county of Basel-Stadt, Switzerland (Permit Numbers: 2375 and 2303).

Reviewing Editor

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

Publication history

  1. Received: August 8, 2016
  2. Accepted: February 6, 2017
  3. Accepted Manuscript published: February 14, 2017 (version 1)
  4. Version of Record published: March 14, 2017 (version 2)

Copyright

© 2017, Favuzza 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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    Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA

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    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 the 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 an 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.

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