Complement evasion is a hallmark of extracellular microbial pathogens such as Borreliella burgdorferi, the causative agent of Lyme disease. Lyme disease spirochetes express nearly a dozen outer surface lipoproteins that bind complement components and interfere with their native activities. Among these, BBK32 is unique in its selective inhibition of the classical pathway. BBK32 blocks activation of this pathway by selectively binding and inhibiting the C1r serine protease of first component of complement, C1. To understand the structural basis for BBK32-mediated C1r inhibition, we performed co-crystallography and size exclusion chromatography-coupled small angle x-ray scattering experiments, which revealed a molecular model of BBK32-C in complex with activated human C1r. Structure-guided site-directed mutagenesis was combined with surface plasmon resonance binding experiments and assays of complement function to validate the predicted molecular interface. The studies reported here, for the first time, provide a structural basis for classical pathway-specific inhibition by a human pathogen.

中文翻译：

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莱姆病螺旋体抑制补体起始蛋白酶 C1r 的结构基础

补体逃避是细胞外微生物病原体的标志，如伯氏疏螺旋体，莱姆病的病原体。莱姆病螺旋体表达近十二种外表面脂蛋白，这些脂蛋白结合补体成分并干扰其天然活性。其中，BBK32 的独特之处在于其对经典途径的选择性抑制。BBK32 通过选择性结合和抑制补体第一成分 C1 的 C1r 丝氨酸蛋白酶来阻断该途径的激活。为了了解 BBK32 介导的 C1r 抑制的结构基础，我们进行了共晶体学和尺寸排阻色谱耦合小角度 X 射线散射实验，揭示了 BBK32-C 与活化的人类 C1r 复合物的分子模型。结构引导的定点诱变与表面等离子体共振结合实验和补体功能测定相结合，以验证预测的分子界面。这里报告的研究首次为人类病原体的经典途径特异性抑制提供了结构基础。