A Structural Basis for Inhibition of the Complement Initiator Protease C1r by Lyme Disease Spirochetes.
A Structural Basis for Inhibition of the Complement Initiator Protease C1r by Lyme Disease Spirochetes.
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DOI：
10.4049/jimmunol.2100815
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发表时间：
2021-12-01
期刊：
影响因子：
--
通讯作者：
Garcia BL
中科院分区：
文献类型：
--
作者：
Garrigues RJ;Powell-Pierce AD;Hammel M;Skare JT;Garcia BL
补体逃避是细胞外微生物病原体如莱姆病病原体伯氏疏螺旋体的标志。莱姆病螺旋体表达近12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，BBK 32在其选择性抑制经典途径方面是独特的。BBK 32通过选择性结合和抑制补体第一组分C1的C1 r丝氨酸蛋白酶来阻断该途径的活化。为了了解BBK 32介导的C1 r抑制的结构基础，我们进行了晶体学和尺寸排阻色谱耦合小角X射线散射实验，揭示了BBK 32-C与活化的人C1 r复合的分子模型。结合表面等离子体共振结合实验和补体功能测定，以验证预测的分子界面的结构指导的定点诱变。结构分析显示BBK 32通过封闭底物相互作用亚位点（即，S1和S1 '），并揭示了C1 r B环对于BBK 32的完全抑制活性的惊人作用。这里报道的研究提供了一个经典的途径特异性抑制的结构基础，由人类病原体。
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 the first component of complement, C1. To understand the structural basis for BBK32-mediated C1r inhibition, we performed 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. Analysis of the structures shows that BBK32 inhibits activated forms of C1r by occluding substrate interaction subsites (i.e., S1 and S1’) and reveals a surprising role for the C1r B loop for full inhibitory activity of BBK32. The studies reported here provide a structural basis for classical pathway-specific inhibition by a human pathogen.
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DOI：
10.1007/978-1-62703-691-7_18
发表时间：
2014
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Dyer, Kevin N;Hammel, Michal;Rambo, Robert P;Tsutakawa, Susan E;Rodic, Ivan;Classen, Scott;Tainer, John A;Hura, Greg L
通讯作者：
Hura, Greg L
体内伯氏毛毛毛毛毛虫的生物发光成像表明，纤连蛋白结合蛋白BBK32是最佳感染性所必需的。
影响因子：
3.6
作者：
Hyde JA;Weening EH;Chang M;Trzeciakowski JP;Höök M;Cirillo JD;Skare JT
通讯作者：
Skare JT
影响因子：
5.7
作者：
Budayova-Spano, M;Grabarse, W;Gaboriaud, C
通讯作者：
Gaboriaud, C
影响因子：
6.4
作者：
FIKRIG, E;BOCKENSTEDT, LK;FLAVELL, RA
通讯作者：
FLAVELL, RA
影响因子：
1.6
作者：
Geisbrecht, BV;Bouyain, S;Pop, M
通讯作者：
Pop, M