Zinc-induced self-association of complement C3b and Factor H: implications for inflammation and age-related macular degeneration.
Zinc-induced self-association of complement C3b and Factor H: implications for inflammation and age-related macular degeneration.
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DOI：
10.1074/jbc.m113.476143
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发表时间：
2013-06-28
期刊：
影响因子：
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通讯作者：
Perkins SJ
中科院分区：
文献类型：
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作者：
Nan R;Tetchner S;Rodriguez E;Pao PJ;Gor J;Lengyel I;Perkins SJ
背景：视网膜下色素上皮沉积物含有补体蛋白和生物可利用锌。结果如下：超离心和X射线散射表明，>100 μm的锌可诱导C3、C3 u和C3 b中的低聚物形成，类似于因子H。结论：锌可沉淀H-C3 b因子复合物，抑制补体激活。意义：阐明了锌诱导视网膜下存款形成的潜在分子机制。视网膜下色素上皮沉积是年龄相关性黄斑变性的标志，含有C3 b和毫摩尔水平的锌。C3是补体的中心蛋白，而C3 u是通过C3中硫酯桥的自发水解形成的。在活化过程中，C3被切割形成活性C3 b，然后C3 b被I因子和H因子灭活，形成C3 c和C3 d片段。锌与C3的相互作用，使用分析ultracenthegation和X-射线散射定量。C3、C3 u和C3 b在>100 μm的锌中强烈缔合，而C3 c和C3 d表现出弱缔合。与锌，C3形成可溶性低聚物，而C3 u和C3 b沉淀。我们得出结论，C3，C3 u和C3 b协会与锌依赖于C3 d和C3 c在每个蛋白质的相对位置。计算预测表明，推定的弱锌结合位点具有不同的能力存在于所有五种蛋白质，与实验一致。因子H在>10 μm的锌中形成大的寡聚体。与单独的C3 b或因子H相比，中心C3 b-因子H复合物的溶解度在60 μm锌下大大降低，在>100 μm锌下甚至更低。锌对C3 b-因子H复合物的去除解释了锌降低的C3 u/C3 b失活速率。锌诱导的沉淀可能有助于视网膜中视网膜下色素上皮沉积的初始发展，以及降低高危患者向晚期年龄相关性黄斑变性的进展。
Background: Sub-retinal pigment epithelial deposits contain complement proteins and bioavailable zinc. Results: Ultracentrifugation and x-ray scattering show that >100 μm zinc induces oligomer formation in each of C3, C3u, and C3b, in analogy to Factor H. Conclusion: Factor H-C3b complexes are precipitated by zinc, which inhibits complement activation. Significance: A potential molecular mechanism for zinc-induced sub-retinal deposit formation is clarified. The sub-retinal pigment epithelial deposits that are a hallmark of age-related macular degeneration contain both C3b and millimolar levels of zinc. C3 is the central protein of complement, whereas C3u is formed by the spontaneous hydrolysis of the thioester bridge in C3. During activation, C3 is cleaved to form active C3b, then C3b is inactivated by Factor I and Factor H to form the C3c and C3d fragments. The interaction of zinc with C3 was quantified using analytical ultracentrifugation and x-ray scattering. C3, C3u, and C3b associated strongly in >100 μm zinc, whereas C3c and C3d showed weak association. With zinc, C3 forms soluble oligomers, whereas C3u and C3b precipitate. We conclude that the C3, C3u, and C3b association with zinc depended on the relative positions of C3d and C3c in each protein. Computational predictions showed that putative weak zinc binding sites with different capacities exist in all five proteins, in agreement with experiments. Factor H forms large oligomers in >10 μm zinc. In contrast to C3b or Factor H alone, the solubility of the central C3b-Factor H complex was much reduced at 60 μm zinc and even more so at >100 μm zinc. The removal of the C3b-Factor H complex by zinc explains the reduced C3u/C3b inactivation rates by zinc. Zinc-induced precipitation may contribute to the initial development of sub-retinal pigment epithelial deposits in the retina as well as reducing the progression to advanced age-related macular degeneration in higher risk patients.