Department of Molecular Biology, University of Aarhus, DK-8000 Aarhus, Denmark.
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3681-6. doi: 10.1073/pnas.0910565107. Epub 2010 Feb 4.
Staphylococcus aureus secretes the SSL7 protein as part of its immune evasion strategy. The protein binds both complement C5 and IgA, yet it is unclear whether SSL7 cross-links these two proteins and, if so, what purpose this serves the pathogen. We have isolated a stable IgA-SSL7-C5 complex, and our crystal structure of the C5-SSL7 complex confirms that binding to C5 occurs exclusively through the C-terminal beta-grasp domain of SSL7 leaving the OB domain free to interact with IgA. SSL7 interacts with C5 >70 A from the C5a cleavage site without inducing significant conformational changes in C5, and efficient inhibition of convertase cleavage of C5 is shown to be IgA dependent. Inhibition of C5a production and bacteriolysis are all shown to require C5 and IgA binding while inhibition of hemolysis is achieved by the C5 binding SSL7 beta-grasp domain alone. These results provide a conceptual and structural basis for the development of a highly specific complement inhibitor preventing only the formation of the lytic membrane attack complex without affecting the important signaling functions of C5a.
金黄色葡萄球菌分泌 SSL7 蛋白作为其免疫逃避策略的一部分。该蛋白结合补体 C5 和 IgA，但尚不清楚 SSL7 是否交联这两种蛋白，如果是这样，这对病原体有何作用。我们已经分离出稳定的 IgA-SSL7-C5 复合物，我们的 C5-SSL7 复合物晶体结构证实，与 C5 的结合仅通过 SSL7 的 C 末端β-抓握结构域发生，使 OB 结构域能够自由与 IgA 相互作用。SSL7 与 C5a 切割位点的 C5 >70 A 相互作用而不诱导 C5 发生显著构象变化，并且显示出有效的转化酶切割 C5 的抑制作用依赖于 IgA。抑制 C5a 的产生和细菌裂解都需要 C5 和 IgA 的结合，而抑制溶血则仅通过 C5 结合 SSL7 的β-抓握结构域来实现。这些结果为开发高度特异性的补体抑制剂提供了概念和结构基础，该抑制剂仅防止形成溶细胞攻击复合物，而不影响 C5a 的重要信号功能。
