A common theme in interaction of bacterial immunoglobulin-binding proteins with immunoglobulins illustrated in the equine system.
A common theme in interaction of bacterial immunoglobulin-binding proteins with immunoglobulins illustrated in the equine system.
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DOI：
10.1074/jbc.m709844200
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发表时间：
2008-06-20
期刊：
影响因子：
--
通讯作者：
Woof JM
中科院分区：
文献类型：
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作者：
Lewis MJ;Meehan M;Owen P;Woof JM
马链球菌亚种的M蛋白。纤维蛋白原结合蛋白（FgBP）是一种与IgG结合的具有抗吞噬活性的细胞壁相关蛋白。7个马IgG亚类的重组版本被用来研究FgBP的亚类特异性。FgBP主要与马IgG4和IgG7结合，很少或没有与其他亚类结合。竞争结合实验显示，FgBP可以抑制葡萄球菌蛋白A和链球菌蛋白G与IgG4和IgG7的结合，暗示Fc结构域间区域与FgBP的结合。为了确定两个IgG Fc结构域中的哪一个促成了与FgBP的相互作用，我们测试了两个人类IgG1/IgA1结构域交换突变体，发现这两个结构域都是完全结合所必需的，其中CH3结构域起着关键作用。利用单点或双点突变的重组马IgG7抗体进一步将FgBP的结合位点定位到CH2-CH3界面残基上。我们发现FgBP与马IgG4和IgG7的相互作用能够破坏C1q结合和抗体介导的经典补体途径的激活，证明了马链球菌逃避免疫应答的有效手段。FgBP与IgG的相互作用模式符合细菌IgG结合蛋白的共同主题。值得注意的是，在详细研究的这些相互作用中，发现所有的IgG结合蛋白都靶向CH2-CH3结构域界面，而不考虑IgG或IgA、链球菌或葡萄球菌来源或宿主物种（马或人）的特异性。
The M protein of Streptococcus equi subsp. equi known as fibrinogen-binding protein (FgBP) is a cell wall-associated protein with antiphagocytic activity that binds IgG. Recombinant versions of the seven equine IgG subclasses were used to investigate the subclass specificity of FgBP. FgBP bound predominantly to equine IgG4 and IgG7, with little or no binding to the other subclasses. Competitive binding experiments revealed that FgBP could inhibit the binding of staphylococcal protein A and streptococcal protein G to both IgG4 and IgG7, implicating the Fc interdomain region in binding to FgBP. To identify which of the two IgG Fc domains contributed to the interaction with FgBP, we tested two human IgG1/IgA1 domain swap mutants and found that both domains are required for full binding, with the CH3 domain playing a critical role. The binding site for FgBP was further localized using recombinant equine IgG7 antibodies with single or double point mutations to residues lying at the CH2-CH3 interface. We found that interaction of FgBP with equine IgG4 and IgG7 was able to disrupt C1q binding and antibody-mediated activation of the classical complement pathway, demonstrating an effective means by which S. equi may evade the immune response. The mode of interaction of FgBP with IgG fits a common theme for bacterial Ig-binding proteins. Remarkably, for those interactions studied in detail, it emerges that all the Ig-binding proteins target the CH2-CH3 domain interface, regardless of specificity for IgG or IgA, streptococcal or staphylococcal origin, or host species (equine or human).