Wu Jin, Wu You-Qiang, Ricklin Daniel, Janssen Bert J C, Lambris John D, Gros Piet
Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Utrecht University, Utrecht, The Netherlands.
Nat Immunol. 2009 Jul;10(7):728-33. doi: 10.1038/ni.1755. Epub 2009 Jun 7.
Factor H (FH) is an abundant regulator of complement activation and protects host cells from self-attack by complement. Here we provide insight into the regulatory activity of FH by solving the crystal structure of the first four domains of FH in complex with its target, complement fragment C3b. FH interacted with multiple domains of C3b, covering a large, extended surface area. The structure indicated that FH destabilizes the C3 convertase by competition and electrostatic repulsion and that FH enables proteolytic degradation of C3b by providing a binding platform for protease factor I while stabilizing the overall domain arrangement of C3b. Our results offer general models for complement regulation and provide structural explanations for disease-related mutations in the genes encoding both FH and C3b.
补体因子H（FH）是补体激活的一种丰富调节因子，可保护宿主细胞免受补体的自身攻击。在此，我们通过解析FH前四个结构域与其靶标补体片段C3b复合物的晶体结构，深入了解了FH的调节活性。FH与C3b的多个结构域相互作用，覆盖了一个大的、延伸的表面积。该结构表明，FH通过竞争和静电排斥使C3转化酶不稳定，并且FH通过为蛋白酶因子I提供结合平台，同时稳定C3b的整体结构域排列，从而实现C3b的蛋白水解降解。我们的结果提供了补体调节的通用模型，并为编码FH和C3b的基因中的疾病相关突变提供了结构解释。
