The PfRCR complex bridges malaria parasite and erythrocyte during invasion

Brendan Farrell, Nawsad Alam, Melissa N. Hart, Abhishek Jamwal, Robert J. Ragotte, Hannah Walters-Morgan, Simon J. Draper, Ellen Knuepfer and Matthew K. Higgins ()
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Brendan Farrell: University of Oxford
Nawsad Alam: University of Oxford
Melissa N. Hart: The Royal Veterinary College
Abhishek Jamwal: University of Oxford
Robert J. Ragotte: University of Oxford
Hannah Walters-Morgan: University of Oxford
Simon J. Draper: University of Oxford
Ellen Knuepfer: The Royal Veterinary College
Matthew K. Higgins: University of Oxford

Nature, 2024, vol. 625, issue 7995, 578-584

Abstract: Abstract The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The PfPCRCR complex1, 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 antibodies3–6 or nanobodies1 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 complex7,8, containing PfRH5, PfCyRPA and PfRIPR, determined by cryogenic-electron microscopy. We test the hypothesis that PfRH5 opens to insert into the membrane9, 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 antibodies5 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 antibodies6, 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.

Date: 2024
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DOI: 10.1038/s41586-023-06856-1

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