8cdd

PfRH5-PfCyRPA-PfRIPR complex from Plasmodium falciparum bound to antibody Cy.003PfRH5-PfCyRPA-PfRIPR complex from Plasmodium falciparum bound to antibody Cy.003

Structural highlights

8cdd is a 5 chain structure with sequence from Gallus gallus and Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RH5IP_PLAF7 Essential for the invasion of host erythrocytes by blood stage merozoites (PubMed:21909261, PubMed:25583518, PubMed:27374406, PubMed:27692771). As part of the PfRH5 adhesion complex, facilitates the interaction of RH5 and human BSG required for the Ca(2+) release into the erythrocyte (PubMed:27374406).^[1] ^[2] ^[3] ^[4]

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.

References

↑ Chen L, Lopaticki S, Riglar DT, Dekiwadia C, Uboldi AD, Tham WH, O'Neill MT, Richard D, Baum J, Ralph SA, Cowman AF. An EGF-like protein forms a complex with PfRh5 and is required for invasion of human erythrocytes by Plasmodium falciparum. PLoS Pathog. 2011 Sep;7(9):e1002199. PMID:21909261 doi:10.1371/journal.ppat.1002199
↑ Reddy KS, Amlabu E, Pandey AK, Mitra P, Chauhan VS, Gaur D. Multiprotein complex between the GPI-anchored CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum erythrocyte invasion. Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1179-84. PMID:25583518 doi:10.1073/pnas.1415466112
↑ Volz JC, Yap A, Sisquella X, Thompson JK, Lim NT, Whitehead LW, Chen L, Lampe M, Tham WH, Wilson D, Nebl T, Marapana D, Triglia T, Wong W, Rogers KL, Cowman AF. Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plasmodium falciparum Invasion of Erythrocytes. Cell Host Microbe. 2016 Jul 13;20(1):60-71. PMID:27374406 doi:10.1016/j.chom.2016.06.004
↑ Ntege EH, Arisue N, Ito D, Hasegawa T, Palacpac NMQ, Egwang TG, Horii T, Takashima E, Tsuboi T. Identification of Plasmodium falciparum reticulocyte binding protein homologue 5-interacting protein, PfRipr, as a highly conserved blood-stage malaria vaccine candidate. Vaccine. 2016 Nov 4;34(46):5612-5622. PMID:27692771 doi:10.1016/j.vaccine.2016.09.028
↑ Farrell B, Alam N, Hart MN, Jamwal A, Ragotte RJ, Walters-Morgan H, Draper SJ, Knuepfer E, Higgins MK. The PfRCR complex bridges malaria parasite and erythrocyte during invasion. Nature. 2024 Jan;625(7995):578-584. PMID:38123677 doi:10.1038/s41586-023-06856-1

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OCA

[1] Chen L, Lopaticki S, Riglar DT, Dekiwadia C, Uboldi AD, Tham WH, O'Neill MT, Richard D, Baum J, Ralph SA, Cowman AF. An EGF-like protein forms a complex with PfRh5 and is required for invasion of human erythrocytes by Plasmodium falciparum. PLoS Pathog. 2011 Sep;7(9):e1002199. PMID:21909261 doi:10.1371/journal.ppat.1002199

[2] Reddy KS, Amlabu E, Pandey AK, Mitra P, Chauhan VS, Gaur D. Multiprotein complex between the GPI-anchored CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum erythrocyte invasion. Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1179-84. PMID:25583518 doi:10.1073/pnas.1415466112

[3] Volz JC, Yap A, Sisquella X, Thompson JK, Lim NT, Whitehead LW, Chen L, Lampe M, Tham WH, Wilson D, Nebl T, Marapana D, Triglia T, Wong W, Rogers KL, Cowman AF. Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plasmodium falciparum Invasion of Erythrocytes. Cell Host Microbe. 2016 Jul 13;20(1):60-71. PMID:27374406 doi:10.1016/j.chom.2016.06.004

[4] Ntege EH, Arisue N, Ito D, Hasegawa T, Palacpac NMQ, Egwang TG, Horii T, Takashima E, Tsuboi T. Identification of Plasmodium falciparum reticulocyte binding protein homologue 5-interacting protein, PfRipr, as a highly conserved blood-stage malaria vaccine candidate. Vaccine. 2016 Nov 4;34(46):5612-5622. PMID:27692771 doi:10.1016/j.vaccine.2016.09.028

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

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