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Cited by 39Malaria Research and ControlErythrocyte Function and PathophysiologyToxoplasma gondii Research Studies

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The PfRCR complex bridges malaria parasite and erythrocyte during invasion

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Farrell, Brendan, Alam, Nawsad, Hart, Melissa N., Jamwal, Abhishek, Ragotte, Robert J., Walters-Morgan, Hannah, Draper, Simon J., Knuepfer, Ellen, Higgins, Matthew K.·2024·Nature
DOI 10.1038/s41586-023-06856-1PMC PMC10794152

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Abstract

The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The PfPCRCR complex 1 , 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 antibodies 3–6 or nanobodies 1 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 complex 7,8 , containing PfRH5, PfCyRPA and PfRIPR, determined by cryogenic-electron microscopy. We test the hypothesis that PfRH5 opens to insert into the membrane 9 , 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 antibodies 5 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 antibodies 6 , 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.

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Metadata

Authors
Farrell, B., Alam, N., Hart, M. N., Jamwal, A., Ragotte, R. J., Walters-Morgan, H., Draper, S. J., Knuepfer, E., & Higgins, M. K.
Affiliations
  • University of Oxford (GB)
  • Royal Veterinary College (GB)
Corresponding author
Higgins, Matthew K.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-12-20
Volume
625
Issue
7995
Pages
578-584
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-06856-1
PMC
PMC10794152
OpenAlex
W4389991849
Cited by
39
References
3
Citations by year
2026: 14 · 2025: 8 · 2024: 14 · 2023: 3
FWCI
9.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • NHS Blood and Transplant
  • Wellcome Trust (220797/Z/20/Z)
  • University of Oxford
  • European Commission (312661, H2020, FP7/2007, 730964)
  • Horizon 2020 Framework Programme (730964)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Health Sciences › Medicine › Physiology (medical) › Erythrocyte Function and Pathophysiology
  • Life Sciences › Immunology and Microbiology › Parasitology › Toxoplasma gondii Research Studies
Keywords
Plasmodium falciparum, erythrocyte invasion, PfRH5, blood-stage malaria vaccine, antibody neutralization, cryo-EM structure, nanobodies
MeSH terms
Animals, Antigens, Protozoan, Carrier Proteins, Disulfides, Erythrocytes, Humans, Malaria, Membrane Proteins, Parasites, Plasmodium falciparum, Protozoan Proteins, Malaria, Falciparum, Malaria Vaccines, Cryoelectron Microscopy, Multiprotein Complexes, Merozoites, Antibodies, Neutralizing

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