Structure of the Pf12 and Pf41 heterodimeric complex of Plasmodium falciparum 6-cysteine proteins.

Melanie H Dietrich, Li-Jin Chan, Amy Adair, Coralie Boulet, Matthew T O'Neill, Li Lynn Tan, Sravya Keremane, Yee-Foong Mok, Alvin W Lo, Paul Gilson, Wai-Hong Tham
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引用次数: 3

Abstract

During the different stages of the Plasmodium life cycle, surface-associated proteins establish key interactions with the host and play critical roles in parasite survival. The 6-cysteine (6-cys) protein family is one of the most abundant surface antigens and expressed throughout the Plasmodium falciparum life cycle. This protein family is conserved across Plasmodium species and plays critical roles in parasite transmission, evasion of the host immune response and host cell invasion. Several 6-cys proteins are present on the parasite surface as hetero-complexes but it is not known how two 6-cys proteins interact together. Here, we present a crystal structure of Pf12 bound to Pf41 at 2.85 Å resolution, two P. falciparum proteins usually found on the parasite surface of late schizonts and merozoites. Our structure revealed two critical interfaces required for complex formation with important implications on how different 6-cysteine proteins may interact with each other. Using structure-function analyses, we identified important residues for Pf12-Pf41 complex formation. In addition, we generated 16 nanobodies against Pf12 and Pf41 and showed that several Pf12-specific nanobodies inhibit Pf12-Pf41 complex formation. Using X-ray crystallography, we were able to describe the structural mechanism of an inhibitory nanobody in blocking Pf12-Pf41 complex formation. Future studies using these inhibitory nanobodies will be useful to determine the functional role of these two 6-cys proteins in malaria parasites.

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恶性疟原虫6-半胱氨酸蛋白Pf12和Pf41异二聚体复合物的结构。
在疟原虫生命周期的不同阶段,表面相关蛋白与宿主建立关键的相互作用,并在寄生虫的生存中发挥关键作用。6-半胱氨酸(6-cys)蛋白家族是最丰富的表面抗原之一,并在整个恶性疟原虫生命周期中表达。该蛋白家族在疟原虫物种中是保守的,在寄生虫传播、逃避宿主免疫反应和宿主细胞入侵中起关键作用。几种6-cys蛋白以异质复合物的形式存在于寄生虫表面,但尚不清楚两种6-cys蛋白如何相互作用。在这里,我们以2.85 Å的分辨率展示了Pf12与Pf41结合的晶体结构,这两种恶性疟原虫蛋白通常存在于晚期分裂体和分裂子的寄生虫表面。我们的结构揭示了复杂形成所需的两个关键界面,这对不同的6-半胱氨酸蛋白如何相互作用具有重要意义。通过结构功能分析,我们确定了Pf12-Pf41复合物形成的重要残基。此外,我们生成了16个针对Pf12和Pf41的纳米体,并表明一些Pf12特异性纳米体抑制Pf12-Pf41复合物的形成。利用x射线晶体学,我们能够描述抑制纳米体阻断Pf12-Pf41复合物形成的结构机制。使用这些抑制纳米体的未来研究将有助于确定这两种6-cys蛋白在疟疾寄生虫中的功能作用。
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来源期刊
CiteScore
3.30
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0.00%
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0
审稿时长
15 weeks
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