Molecular basis for complement recognition and inhibition determined by crystallographic studies of the staphylococcal complement inhibitor (SCIN) bound to C3c and C3b.
Molecular basis for complement recognition and inhibition determined by crystallographic studies of the staphylococcal complement inhibitor (SCIN) bound to C3c and C3b.
复制标题
DOI：
10.1016/j.jmb.2010.07.029
复制
发表时间：
2010-09-10
影响因子：
5.6
通讯作者：
Geisbrecht BV
中科院分区：
文献类型：
--
作者：
Garcia BL;Ramyar KX;Tzekou A;Ricklin D;McWhorter WJ;Lambris JD;Geisbrecht BV
人补体系统通过标记和消除微生物入侵者在先天性和适应性免疫中起着重要作用。外源表面上补体的活化导致补体组分3（C3）蛋白水解裂解成有效的调理素C3b，其触发多种免疫应答并参与由称为C3转化酶的多蛋白组装介导的自扩增环。人类病原体金黄色葡萄球菌已经进化出一种复杂且有效的补体逃避策略，该策略基于一系列有效的抑制蛋白。其中之一，葡萄球菌补体抑制剂（SCIN），作用于C3转化酶（C3bBb）的水平，并通过将转化酶捕获在稳定但无活性的状态来损害下游补体功能。以前，我们已经表明，SCIN结合C3 B直接和竞争性抑制人因子H的结合，并在较小程度上抑制因子B与C3 B的结合。在这里，我们报告的SCIN结合C3b和C3c的共晶结构在7.5和3.5 μ m的极限分辨率，分别，并表明SCIN结合C3b的关键功能区。最重要的是，SCIN结合位点在空间上封闭fH和fB的结合位点。我们的研究结果提供了深入了解SCIN结合活化衍生物的C3，解释如何SCIN可以识别C3b在没有其他补体成分，并提供了竞争性C3b结合特性的SCIN的结构基础。在未来，这可能会建议基于SCIN结构的新型补体抑制剂的设计模板。
The human complement system plays an essential role in innate and adaptive immunity by marking and eliminating microbial intruders. Activation of complement on foreign surfaces results in proteolytic cleavage of complement component 3 (C3) into the potent opsonin C3b, which triggers a variety of immune responses and participates in a self-amplification loop mediated by a multi-protein assembly known as the C3 convertase. The human pathogen Staphylococcus aureus has evolved a sophisticated and potent complement evasion strategy, which is predicated upon an arsenal of potent inhibitory proteins. One of these, the Staphylococcal Complement INhibitor (SCIN), acts at the level of the C3 convertase (C3bBb) and impairs downstream complement function by trapping the convertase in a stable but inactive state. Previously, we have shown that SCIN binds C3b directly and competitively inhibits binding of human factor H, and to a lesser degree that of factor B to C3b. Here, we report the co-crystal structures of SCIN bound to C3b and C3c at 7.5 and 3.5 Å limiting resolution, respectively, and show that SCIN binds a critical functional area on C3b. Most significantly, the SCIN binding site sterically occludes the binding sites of both fH and fB. Our results give insight into SCIN binding to activated derivatives of C3, explain how SCIN can recognize C3b in the absence of other complement components, and provide a structural basis for the competitive C3b-binding properties of SCIN. In the future, this may suggest templates for the design of novel complement inhibitors based upon the SCIN structure.
登录
查看更多内容
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
11.4
作者：
Janssen, Bert J. C.;Gomes, Lucio;Gros, Piet
通讯作者：
Gros, Piet
影响因子：
6.7
作者：
Chavakis, T;Wiechmann, K;Herrmann, M
通讯作者：
Herrmann, M
DOI：
10.1084/jem.20070818
发表时间：
2007-10-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jongerius I;Köhl J;Pandey MK;Ruyken M;van Kessel KP;van Strijp JA;Rooijakkers SH
通讯作者：
Rooijakkers SH
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC