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标题：Multiprotein complex between the GPI-anchored CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum erythrocyte invasion
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作者：K. Sony Reddy ; Emmanuel Amlabu ; Alok K. Pandey 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：4
页码：1179-1184
DOI：10.1073/pnas.1415466112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificancePlasmodium falciparum reticulocyte binding-like homologous protein 5 (PfRH5) is a leading blood-stage malaria vaccine candidate that elicits potent strain-transcending invasion inhibitory antibodies. However, it lacks both transmembrane domains and a GPI-anchor and is thus anchored to the merozoite surface through an unknown mechanism. We have demonstrated that PfRH5 and its known partner, PfRH5-interacting protein (PfRipr), associates with a conserved GPI-anchored protein, Cysteine-rich protective antigen (CyRPA), to form a complex on the merozoite surface. CyRPA was shown to be GPI-linked, refractory to knockout, and like PfRH5, elicited potent strain-transcending invasion inhibitory antibodies. This discovery elucidates the formation of a previously unidentified PfRH5/PfRipr/CyRPA protein complex on the merozoite surface, which facilitates the PfRH5-Basigin interaction and offers another highly conserved, potent target (CyRPA) for novel antimalarial strategies that could abrogate formation of this crucial complex. Erythrocyte invasion by Plasmodium falciparum merozoites is a highly intricate process in which Plasmodium falciparum reticulocyte binding-like homologous protein 5 (PfRH5) is an indispensable parasite ligand that binds with its erythrocyte receptor, Basigin. PfRH5 is a leading blood-stage vaccine candidate because it exhibits limited polymorphisms and elicits potent strain-transcending parasite neutralizing antibodies. However, the mechanism by which it is anchored to the merozoite surface remains unknown because both PfRH5 and the PfRH5-interacting protein (PfRipr) lack transmembrane domains and GPI anchors. Here we have identified a conserved GPI-linked parasite protein, Cysteine-rich protective antigen (CyRPA) as an interacting partner of PfRH5-PfRipr that tethers the PfRH5/PfRipr/CyRPA multiprotein complex on the merozoite surface. CyRPA was demonstrated to be GPI-linked, localized in the micronemes, and essential for erythrocyte invasion. Specific antibodies against the three proteins successfully detected the intact complex in the parasite and coimmunoprecipitated the three interacting partners. Importantly, full-length CyRPA antibodies displayed potent strain-transcending invasion inhibition, as observed for PfRH5. CyRPA does not bind with erythrocytes, suggesting that its parasite neutralizing antibodies likely block its critical interaction with PfRH5-PfRipr, leading to a blockade of erythrocyte invasion. Further, CyRPA and PfRH5 antibody combinations produced synergistic invasion inhibition, suggesting that simultaneous blockade of the PfRH5-Basigin and PfRH5/PfRipr/CyRPA interactions produced an enhanced inhibitory effect. Our discovery of the critical interactions between PfRH5, PfRipr, and the GPI-anchored CyRPA clearly defines the components of the essential PfRH5 adhesion complex for P. falciparum erythrocyte invasion and offers it as a previously unidentified potent target for antimalarial strategies that could abrogate formation of the crucial multiprotein complex.
关键词：malaria ; erythrocyte invasion ; protein–protein interactions ; blood-stage vaccines ; PfRH5