CspZ变体与因子H的特异性相互作用结合了一个金属位点,支持莱姆包虫病补体规避。

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Kalvis Brangulis, Valerie Sürth, Ashley L Marcinkiewicz, Inara Akopjana, Andris Kazaks, Janis Bogans, Alisa Huber, Yi-Pin Lin, Peter Kraiczy
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引用次数: 0

摘要

多态微生物免疫逃避蛋白决定了病原体的物种或菌株特异性毒力。金属可影响微生物蛋白如何赋予宿主-病原体相互作用,但这种活性是否可等位基因变异尚不清楚。在这里,我们研究了莱姆病(LD)螺旋体细菌的多态 CspZ 蛋白,以评估金属在蛋白质-蛋白质相互作用中的作用。CspZ通过与补体调节因子H(FH)结合,有助于逃避免疫防御的第一道防线--补体系统。通过获得高分辨率的 CspZ-FH 共晶体结构,我们发现了一个锌元素,它能协调 FH SCR6-7 结构域与 B. burgdorferi B31 的 CspZ 环路上的 Glu65 的结合。然而,对于具有不同环向和/或缺乏该谷氨酸的 CspZ 直向同源物,锌对于人类 FH 的结合是不可或缺的。对所有已知的与人类 FH 结合的 CspZ 变体进行的系统发育分析进一步将这些蛋白分为三个与环序列相关的独特谱系。这表明多种 FH 结合机制是通过 LD 螺旋体-宿主相互作用进化而来的。总之,这项多学科工作阐明了金属的等位基因特异性免疫逃避作用如何受到微生物蛋白质多态性的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CspZ variant-specific interaction with Factor H incorporates a metal site to support Lyme borreliae complement evasion.

Polymorphic microbial immune evasion proteins dictate the pathogen species- or strain-specific virulence. Metals can impact how microbial proteins confer host-pathogen interactions, but whether this activity can be allelically variable is unclear. Here, we investigate the polymorphic CspZ protein of Lyme disease (LD) spirochete bacteria to assess the role of metals in protein-protein interaction. CspZ facilitates evasion of the complement system, the first-line of immune defense through binding to the complement regulator Factor H (FH). By obtaining a high-resolution co-crystal CspZ-FH structure, we identified a zinc coordinating the binding of FH SCR6-7 domains to a Glu65 on a loop from CspZ of B. burgdorferi B31. However, zinc is dispensable for human FH binding for CspZ orthologs with a different loop orientation and/or lacking this glutamate. Phylogenetic analysis of all known human FH binding CspZ variants further grouped the proteins into three unique lineages correlating with loop sequences. This suggests multiple FH-binding mechanisms evolved through LD spirochete-host interactions. Overall, this multidisciplinary work elucidates how the allelically-specific immune evasion role of metals is impacted by microbial protein polymorphisms.

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来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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