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疟疾疫苗候选抗原CyRPA的结构及其与寄生虫入侵抑制抗体的复合物

Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody.

作者信息

Favuzza Paola, Guffart Elena, Tamborrini Marco, Scherer Bianca, Dreyer Anita M, Rufer Arne C, Erny Johannes, Hoernschemeyer Joerg, Thoma Ralf, Schmid Georg, Gsell Bernard, Lamelas Araceli, Benz Joerg, Joseph Catherine, Matile Hugues, Pluschke Gerd, Rudolph Markus G

机构信息

Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland.

University of Basel, Basel, Switzerland.

出版信息

Elife. 2017 Feb 14;6:e20383. doi: 10.7554/eLife.20383.

DOI:10.7554/eLife.20383
PMID:28195038
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5349852/
Abstract

Invasion of erythrocytes by merozoites is a composite process involving the interplay of several proteins. Among them, the Cysteine-Rich Protective Antigen (PfCyRPA) is a crucial component of a ternary complex, including Reticulocyte binding-like Homologous protein 5 (PfRH5) and the RH5-interacting protein (PfRipr), essential for erythrocyte invasion. Here, we present the crystal structures of PfCyRPA and its complex with the antigen-binding fragment of a parasite growth inhibitory antibody. PfCyRPA adopts a 6-bladed β-propeller structure with similarity to the classic sialidase fold, but it has no sialidase activity and fulfills a purely non-enzymatic function. Characterization of the epitope recognized by protective antibodies may facilitate design of peptidomimetics to focus vaccine responses on protective epitopes. Both in vitro and in vivo anti-PfCyRPA and anti-PfRH5 antibodies showed more potent parasite growth inhibitory activity in combination than on their own, supporting a combined delivery of PfCyRPA and PfRH5 in vaccines.

摘要

疟原虫裂殖子侵入红细胞是一个复杂的过程，涉及多种蛋白质的相互作用。其中，富含半胱氨酸的保护性抗原（PfCyRPA）是三元复合物的关键组成部分，该复合物包括网织红细胞结合样同源蛋白5（PfRH5）和RH5相互作用蛋白（PfRipr），它们对红细胞侵入至关重要。在此，我们展示了PfCyRPA及其与寄生虫生长抑制抗体抗原结合片段复合物的晶体结构。PfCyRPA采用6叶β-螺旋桨结构，与经典唾液酸酶折叠相似，但它没有唾液酸酶活性，仅发挥纯粹的非酶功能。对保护性抗体识别的表位进行表征可能有助于设计拟肽，使疫苗反应聚焦于保护性表位。体外和体内抗PfCyRPA和抗PfRH5抗体联合使用时比单独使用显示出更强的寄生虫生长抑制活性，这支持在疫苗中联合递送PfCyRPA和PfRH5。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/6714ea669249/elife-20383-resp-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/c5711c83d2c2/elife-20383-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/004282bd7f05/elife-20383-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/150556800d54/elife-20383-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/58f060f811fd/elife-20383-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/7be54cc70d10/elife-20383-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/6693e7cc60b5/elife-20383-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/9ec91250f8d3/elife-20383-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/273104435c4b/elife-20383-fig3-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/c2bbe14ed682/elife-20383-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/e42fbcdc15db/elife-20383-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/546f85c1ca48/elife-20383-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/fb858791faf3/elife-20383-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/03f2ce1b098d/elife-20383-fig5-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/02dd1ace12e3/elife-20383-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/141bca2188f8/elife-20383-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/f563ea3877b6/elife-20383-resp-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/6885e0290e5b/elife-20383-resp-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/8d013d7ab7d2/elife-20383-resp-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/6714ea669249/elife-20383-resp-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/c5711c83d2c2/elife-20383-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/004282bd7f05/elife-20383-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/150556800d54/elife-20383-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/58f060f811fd/elife-20383-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/7be54cc70d10/elife-20383-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/6693e7cc60b5/elife-20383-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/9ec91250f8d3/elife-20383-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/273104435c4b/elife-20383-fig3-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/c2bbe14ed682/elife-20383-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/e42fbcdc15db/elife-20383-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/546f85c1ca48/elife-20383-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/fb858791faf3/elife-20383-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/03f2ce1b098d/elife-20383-fig5-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/02dd1ace12e3/elife-20383-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/141bca2188f8/elife-20383-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/f563ea3877b6/elife-20383-resp-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/6885e0290e5b/elife-20383-resp-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/8d013d7ab7d2/elife-20383-resp-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b84/5349852/6714ea669249/elife-20383-resp-fig5.jpg

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