Identification of peptidic inhibitors of the alternative complement pathway based on Staphylococcus aureus SCIN proteins.
Identification of peptidic inhibitors of the alternative complement pathway based on Staphylococcus aureus SCIN proteins.
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基于金黄色葡萄球菌 SCIN 蛋白的补体旁路肽抑制剂的鉴定。
DOI：
10.1016/j.molimm.2015.05.012
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发表时间：
2015
影响因子：
3.6
通讯作者：
Geisbrecht,BrianV
中科院分区：
文献类型：
--
作者：
Summers,BradyJ;Garcia,BrandonL;Woehl,JordanL;Ramyar,KasraX;Yao,Xiaolan;Geisbrecht,BrianV
补体系统在许多人类炎症性疾病中起着核心作用，因此迫切需要开发补体导向的治疗方法。病原体金黄色葡萄球菌分泌的抗补体蛋白库的发现带来了利用这些分子的强大抑制特性的潜力。其中一类抑制剂，SCINs，与C3b表面的一个功能性“热点”相互作用。SCINs不仅稳定了替代途径（AP） C3转化酶（C3bBb）的失活形式，而且还重叠了补体因子B和h的C3b结合位点。在这里，我们确定了SCINs中一个保守的Arg残基对全长SCIN蛋白的功能至关重要。尽管如此，我们还发现在C3b接触位点发现的其他残基的贡献存在scin特异性差异，这表明更多样化的残基库可能能够识别C3b的这一区域。为了研究这种可能性，我们进行了一项噬菌体显示筛选，目的是鉴定与scin竞争的12-mer肽。总共鉴定出7个独特的序列，它们都与C3b直接结合。在补体功能测定中，其中一部分特异性抑制AP。通过表面等离子体共振方法探索了这些肽抑制AP的机制，发现7种肽中有6种通过干扰因子B/C3b的结合来破坏C3bBb的形成。据我们所知，这项研究已经确定了第一个小分子，保留较大的葡萄球菌免疫逃避蛋白的抑制特性。
The complement system plays a central role in a number of human inflammatory diseases, and there is a significant need for development of complement-directed therapies. The discovery of an arsenal of anti-complement proteins secreted by the pathogenStaphylococcus aureusbrought with it the potential for harnessing the powerful inhibitory properties of these molecules. One such family of inhibitors, the SCINs, interact with a functional “hot-spot” on the surface of C3b. SCINs not only stabilize an inactive form of the alternative pathway (AP) C3 convertase (C3bBb), but also overlap the C3b binding site of complement factors B and H. Here we determined that a conserved Arg residue in SCINs is critical for function of full-length SCIN proteins. Despite this, we also found SCIN-specific differences in the contributions of other residues found at the C3b contact site, which suggested that a more diverse repertoire of residues might be able to recognize this region of C3b. To investigate this possibility, we conducted a phage display screen aimed at identifying SCIN-competitive 12-mer peptides. In total, seven unique sequences were identified and all exhibited direct C3b binding. A subset of these specifically inhibited the AP in assays of complement function. The mechanism of AP inhibition by these peptides was probed through surface plasmon resonance approaches, which revealed that six of the seven peptides disrupted C3bBb formation by interfering with factor B/C3b binding. To our knowledge this study has identified the first small molecules that retain inhibitory properties of larger staphylococcal immune evasion proteins.
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葡萄球菌补体抑制剂 (SCIN) 蛋白家族的 C3b 转化酶接触残基和三级结构的多样性*
影响因子：
4.8
作者：
B. Garcia;B. Summers;Zhuoer Lin;K. Ramyar;Daniel Ricklin;Divya V. Kamath;Z. Fu;John D Lambris;B. Geisbrecht
通讯作者：
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影响因子：
20.3
作者：
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通讯作者：
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影响因子：
16.1
作者：
Ekdahl, Kristina N.;Lambris, John D.;Elwing, Hans;Ricklin, Daniel;Nilsson, Per H.;Teramura, Yuji;Nicholls, Ian A.;Nilsson, Bo
通讯作者：
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影响因子：
16.8
作者：
Nilsson B;Korsgren O;Lambris JD;Ekdahl KN
通讯作者：
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