Institute of Structural and Molecular Biology, School of Biological Sciences, King's Buildings, University of Edinburgh, Edinburgh, United Kingdom.
PLoS One. 2012;7(2):e32187. doi: 10.1371/journal.pone.0032187. Epub 2012 Feb 28.
Factor H (FH) is a soluble regulator of the human complement system affording protection to host tissues. It selectively inhibits amplification of C3b, the activation-specific fragment of the abundant complement component C3, in fluid phase and on self-surfaces and accelerates the decay of the alternative pathway C3 convertase, C3bBb. We have determined the crystal structure of the three carboxyl-terminal complement control protein (CCP) modules of FH (FH18-20) that bind to C3b, and which additionally recognize polyanionic markers specific to self-surfaces. These CCPs harbour nearly 30 disease-linked missense mutations. We have also deployed small-angle X-ray scattering (SAXS) to investigate FH18-20 flexibility in solution using FH18-20 and FH19-20 constructs. In the crystal lattice FH18-20 adopts a "J"-shape: A ~122-degree tilt between the structurally highly similar modules 18 and 19 precedes an extended, linear arrangement of modules 19 and 20 as observed in previously determined structures of these two modules alone. However, under solution conditions FH18-20 adopts multiple conformations mediated by flexibility between CCPs 18 and 19. We also pinpoint the locations of disease-associated missense mutations on the module 18 surface and discuss our data in the context of the C3b:FH interaction.
补体因子 H（FH）是一种可溶性的人类补体系统调节剂，可为宿主组织提供保护。它选择性地抑制 C3b 的扩增，C3b 是丰富的补体成分 C3 的激活特异性片段，在流体相和自身表面，并加速替代途径 C3 转化酶，C3bBb 的衰变。我们已经确定了 FH（FH18-20）结合 C3b 的三个羧基末端补体控制蛋白（CCP）模块的晶体结构，这些模块还识别特定于自身表面的多阴离子标记物。这些 CCP 含有近 30 个与疾病相关的错义突变。我们还使用 SAXS 技术（小角度 X 射线散射）研究了 FH18-20 在溶液中的灵活性，使用了 FH18-20 和 FH19-20 构建体。在晶体晶格中，FH18-20 采用“J”形：结构高度相似的模块 18 和 19 之间约 122 度的倾斜，然后是模块 19 和 20 的延伸线性排列，如单独确定的这两个模块的结构所示。然而，在溶液条件下，FH18-20 通过 CCP 18 和 19 之间的灵活性采用多种构象。我们还确定了位于模块 18 表面的与疾病相关的错义突变的位置，并在 C3b：FH 相互作用的背景下讨论了我们的数据。
