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Publication Abstract from PubMed

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.

The PfRCR complex bridges malaria parasite and erythrocyte during invasion.,Farrell B, Alam N, Hart MN, Jamwal A, Ragotte RJ, Walters-Morgan H, Draper SJ, Knuepfer E, Higgins MK Nature. 2024 Jan;625(7995):578-584. doi: 10.1038/s41586-023-06856-1. Epub 2023 , Dec 20. PMID:38123677^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.