Cryo-EM structure of endogenous Plasmodium falciparum Pfs230 and Pfs48/45 fertilization complex

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-07-31 DOI:10.1126/science.ady0241

Melanie H. Dietrich, Jill Chmielewski, Li-Jin Chan, Li Lynn Tan, Amy Adair, Frankie M. T. Lyons, Mikha Gabriela, Sash Lopaticki, Toby A. Dite, Laura F. Dagley, Lucia Pazzagli, Priya Gupta, Mohd Kamil, Ashley M. Vaughan, Rattanaporn Rojrung, Anju Abraham, Ramin Mazhari, Rhea J. Longley, Kathleen Zeglinski, Quentin Gouil, Ivo Mueller, Stewart A. Fabb, Rekha Shandre-Mugan, Colin W. Pouton, Alisa Glukhova, Shabih Shakeel, Wai-Hong Tham

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Abstract

Malaria parasite fertilization occurs in the midgut of a female Anopheles mosquito. Blocking fertilization within the mosquito can prevent malaria transmission. Plasmodium falciparum Pfs230 and Pfs48/45 proteins are critical for male fertility and transmission of the malaria parasite. They form a core fertilization complex, but it is unknown how they interact. We determined a cryo–electron microscopy structure of the endogenous Pfs230-Pfs48/45 complex showing that Pfs48/45 interacts with Pfs230 domains 13 and 14. Transgenic parasite lines with these domains removed were defective in Pfs230 gamete localization and showed reduced oocyst formation. Nanobodies against domains 13 and 14 inhibited Pfs230-Pfs48/45 complex formation and reduced transmission, and structural analyses revealed their epitopes. These Pfs230 domains were targets of naturally acquired immunity and immune sera from messenger RNA lipid nanoparticle immunizations blocked parasite transmission.

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内源性恶性疟原虫Pfs230和Pfs48/45受精复合物的低温电镜结构

疟疾寄生虫受精发生在雌性按蚊的中肠。阻断蚊子体内的受精可以防止疟疾的传播。恶性疟原虫Pfs230和Pfs48/45对男性生育力和疟原虫传播至关重要。它们形成了一个核心受精复合体，但它们是如何相互作用的尚不清楚。我们确定了内源性Pfs230-Pfs48/45复合物的低温电镜结构，显示Pfs48/45与Pfs230结构域13和14相互作用。去除这些结构域的转基因寄生虫系在Pfs230配子定位上存在缺陷，卵囊形成减少。结构域13和14的纳米体抑制了Pfs230-Pfs48/45复合物的形成，减少了传输，结构分析揭示了它们的表位。这些Pfs230结构域是自然获得性免疫的靶点，mrna -脂质纳米颗粒免疫的免疫血清阻断了寄生虫的传播。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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