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.

中文翻译：

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CspZ 变体特异性与 Factor H 的相互作用包含一个金属位点以支持莱姆疏螺旋体补体逃避。


多态性微生物免疫逃避蛋白决定了病原体物种或菌株特异性的毒力。金属可以影响微生物蛋白质如何赋予宿主-病原体相互作用，但这种活性是否可以等位变化尚不清楚。在这里，我们研究了莱姆病 （LD） 螺旋体细菌的多态性 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，促进补体系统的逃避，补体系统是免疫防御的第一道防线。通过获得高分辨率共晶体 CspZ-FH 结构，我们鉴定了一种锌，该锌协调 FH SCR6-7 结构域与伯氏疏螺旋体 B31 CspZ 环上 Glu65 的结合。然而，锌对于具有不同环方向和/或缺乏这种谷氨酸的 CspZ 直系同源物的人类 FH 结合是必不可少的。对所有已知的人类 FH 结合 CspZ 变体的系统发育分析进一步将蛋白质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。总体而言，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。