biostudies-literatureScally SWDepartment of Health | National Health and Medical Research CouncilWellcome Trust2039-2053https://www.ebi.ac.uk/biostudies/studies/S-EPMC9712106biostudies-literatureUnknown7(12)The most severe form of malaria is caused by Plasmodium falciparum. These parasites invade human erythrocytes, and an essential step in this process involves the ligand PfRh5, which forms a complex with cysteine-rich protective antigen (CyRPA) and PfRh5-interacting protein (PfRipr) (RCR complex) and binds basigin on the host cell. We identified a heteromeric disulfide-linked complex consisting of P. falciparum Plasmodium thrombospondin-related apical merozoite protein (PfPTRAMP) and P. falciparum cysteine-rich small secreted protein (PfCSS) and have shown that it binds RCR to form a pentameric complex, PCRCR. Using P. falciparum lines with conditional knockouts, invasion inhibitory nanobodies to both PfPTRAMP and PfCSS, and lattice light-sheet microscopy, we show that they are essential foNature microbiologyPCRCR complex is essential for invasion of human erythrocytes by Plasmodium falciparum.PMC9712106206515/Z/17/Z1173049637406Rogers KLEvelyn CScally SWGeoghegan NDAdair ACowman AFPasternak MHealer JTriglia TSeager BADagley LFLim PSTham WHfalsePCRCR complex is essential for invasion of human erythrocytes by Plasmodium falciparum.The most severe form of malaria is caused by Plasmodium falciparum. These parasites invade human erythrocytes, and an essential step in this process involves the ligand PfRh5, which forms a complex with cysteine-rich protective antigen (CyRPA) and PfRh5-interacting protein (PfRipr) (RCR complex) and binds basigin on the host cell. We identified a heteromeric disulfide-linked complex consisting of P. falciparum Plasmodium thrombospondin-related apical merozoite protein (PfPTRAMP) and P. falciparum cysteine-rich small secreted protein (PfCSS) and have shown that it binds RCR to form a pentameric complex, PCRCR. Using P. falciparum lines with conditional knockouts, invasion inhibitory nanobodies to both PfPTRAMP and PfCSS, and lattice light-sheet microscopy, we show that they are essential fo2022-01-01T00:00:00Z2022 Dec2026-05-28T21:28:52.661Z2025-04-19T22:48:46.968ZS-EPMC97121063639694210.1038/s41564-022-01261-2