Department of Structural and Molecular Biology, University College London, London, UK.
Adv Exp Med Biol. 2010;703:25-47. doi: 10.1007/978-1-4419-5635-4_3.
Factor H (FH) is the major regulator of the central complement protein C3b in the alternative pathway of complement activation, and is comprised of 20 SCR domains. A FH Tyr402His polymorphism in SCR-7 is associated with age-related macular degeneration (AMD) and leads to deposition of complement in drusen. The unravelling of how FH interacts with five major physiological and patho-physiological ligands is complicated by the weak nature of these interactions, coupled with the multivalency of FH. Using multiple biophysical methods, we summarise our recent results for these five FH ligands: (1) FH by itself shows a folded-back SCR domain structure in solution, and self-associates in a manner dependent on electrostatic forces. (2) FH activity is inhibited by zinc, which causes FH to aggregate. The onset of FH-zinc aggregation for zinc concentrations above 20 muM appears to be enhanced with the His402 allotype, and may be relevant to AMD. (3) The FH and C-reactive protein (CRP) interaction has been controversial; however our new work resolves earlier discrepancies. The FH-CRP interaction is only observed when native CRP is at high acute-phase concentration levels, and CRP binds weakly to the His402 FH allotype to suggest a molecular mechanism that leads to AMD. (4) Heparin is an analogue of the polyanionic host cell surface, and FH forms higher oligomers with larger heparin fragments, suggesting a mechanism for more effective FH regulation. (5) The interaction of C3b with FH also depends on buffer, and FH forms multimers with the C3d fragment of C3b. This FH-C3d interaction at high FH concentration may also facilitate complement regulation. Overall, our results to date suggest that the FH interactions involving zinc and native CRP have the closest relevance for explaining the onset of AMD.
补体因子 H（FH）是补体激活旁路途径中中心补体蛋白 C3b 的主要调节剂，由 20 个 SCR 结构域组成。SCR-7 中的 FH Tyr402His 多态性与年龄相关性黄斑变性（AMD）有关，并导致补体在 drusen 中沉积。FH 与五种主要生理和病理生理配体相互作用的机制非常复杂，这是由于这些相互作用的强度较弱，加上 FH 的多价性。使用多种生物物理方法，我们总结了最近关于这五种 FH 配体的研究结果：（1）FH 本身在溶液中显示出折叠回的 SCR 结构域结构，并以依赖于静电力的方式自组装。（2）锌抑制 FH 的活性，导致 FH 聚集。对于锌浓度高于 20 μM 的 FH-锌聚集的起始似乎与 His402 同种型增强有关，这可能与 AMD 有关。（3）FH 与 C 反应蛋白（CRP）的相互作用一直存在争议；然而，我们的新工作解决了早期的差异。只有在天然 CRP 处于高急性期浓度水平时，才会观察到 FH-CRP 相互作用，而 CRP 弱结合于 His402 FH 同种型，提示了导致 AMD 的分子机制。（4）肝素是多阴离子宿主细胞表面的类似物，FH 与较大的肝素片段形成更高的寡聚物，这表明了一种更有效的 FH 调节机制。（5）C3b 与 FH 的相互作用也依赖于缓冲液，并且 FH 与 C3b 的 C3d 片段形成多聚体。在高 FH 浓度下，这种 FH-C3d 相互作用也可能促进补体调节。总的来说，我们目前的研究结果表明，涉及锌和天然 CRP 的 FH 相互作用最能解释 AMD 的发病机制。
