Outer surface lipoproteins from the Lyme disease spirochete exploit the molecular switch mechanism of the complement protease C1s.
Outer surface lipoproteins from the Lyme disease spirochete exploit the molecular switch mechanism of the complement protease C1s.
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DOI：
10.1016/j.jbc.2022.102557
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发表时间：
2022-11
影响因子：
4.8
通讯作者：
Garcia, Brandon L.
中科院分区：
文献类型：
--
作者：
Garrigues, Ryan J.;Thomas, Sheila;Leong, John M.;Garcia, Brandon L.
蛋白水解级联包括几个重要的生理系统，包括称为补体级联的先天免疫的主要分支。为了防止补体介导的攻击，莱姆病的病原体伯氏疏螺旋体（Borreliella burgdorferi）产生许多有助于成功逃避补体的外表面定位的脂蛋白。最近，我们发现了一对B. burgdorferi表面脂蛋白的OspEF相关蛋白家族-称为Elp B和ElpQ-抑制抗体介导的补体激活。在这项研究中，我们研究了ElpB和ElpQ补体抑制的分子机制，使用一系列的生物化学和生物物理方法。补体激活的体外测定显示，每个Elp蛋白的独立折叠的同源C-末端结构域保持完全的补体抑制活性，并选择性地抑制经典途径。使用结合试验和补体成分C1 s酶测定，我们表明，ELP蛋白的结合激活C1 s块补体成分C4裂解竞争C1 s-C4结合，而不闭塞的活性位点。C1 s介导的C4裂解依赖于激活诱导的结合位点，称为外切位点。为了测试这些exosite是否参与Elp-C1 s结合，我们进行了定点诱变，这表明ElpB和ElpQ结合需要C1 s残基的阴离子结合exosite位于C1 s的丝氨酸蛋白酶结构域。基于这些结果，我们提出了一个模型，ElpB和ElpQ利用激活诱导的构象变化，通常是重要的C1 s介导的C4裂解。我们的研究扩展了已知的微生物病原体的补体逃避机制，并揭示了莱姆病螺旋体选择性C1 s抑制的新分子机制。
Proteolytic cascades comprise several important physiological systems, including a primary arm of innate immunity called the complement cascade. To safeguard against complement-mediated attack, the etiologic agent of Lyme disease, Borreliella burgdorferi, produces numerous outer surface–localized lipoproteins that contribute to successful complement evasion. Recently, we discovered a pair of B. burgdorferi surface lipoproteins of the OspEF-related protein family—termed ElpB and ElpQ—that inhibit antibody-mediated complement activation. In this study, we investigate the molecular mechanism of ElpB and ElpQ complement inhibition using an array of biochemical and biophysical approaches. In vitro assays of complement activation show that an independently folded homologous C-terminal domain of each Elp protein maintains full complement inhibitory activity and selectively inhibits the classical pathway. Using binding assays and complement component C1s enzyme assays, we show that binding of Elp proteins to activated C1s blocks complement component C4 cleavage by competing with C1s–C4 binding without occluding the active site. C1s-mediated C4 cleavage is dependent on activation-induced binding sites, termed exosites. To test whether these exosites are involved in Elp–C1s binding, we performed site-directed mutagenesis, which showed that ElpB and ElpQ binding require C1s residues in the anion-binding exosite located on the serine protease domain of C1s. Based on these results, we propose a model whereby ElpB and ElpQ exploit activation-induced conformational changes that are normally important for C1s-mediated C4 cleavage. Our study expands the known complement evasion mechanisms of microbial pathogens and reveals a novel molecular mechanism for selective C1s inhibition by Lyme disease spirochetes.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
3.2
作者：
Dowdell, Alexander S.;Murphy, Maxwell D.;Zuckert, Wolfram R.
通讯作者：
Zuckert, Wolfram R.
影响因子：
3.6
作者：
Hartmann, Kristina;Corvey, Carsten;Kraiczy, Peter
通讯作者：
Kraiczy, Peter
影响因子：
1.6
作者：
Geisbrecht, BV;Bouyain, S;Pop, M
通讯作者：
Pop, M
DOI：
10.4049/jimmunol.2100815
发表时间：
2021-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Garrigues RJ;Powell-Pierce AD;Hammel M;Skare JT;Garcia BL
通讯作者：
Garcia BL