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首页> 外文期刊>Journal of Molecular Biology >Implications of the progressive self-association of wild-type human factor H6 for complement regulation and disease
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Implications of the progressive self-association of wild-type human factor H6 for complement regulation and disease

机译：野生型人类因子H6的进行性自我关联对补体调节和疾病的影响

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Factor H (FH) is a major regulator of complement alternative pathway activation. It is composed of 20 short complement regulator (SCR) domains and is genetically associated as a risk factor for age-related macular degeneration. Previous studies on FH suggested that it existed in monomeric and dimeric forms. Improved X-ray scattering and analytical ultracentrifugation methodology for wild-type FH permitted a clarification of these oligomeric properties. Data at lower concentrations revealed a dependence of the X-ray radius of gyration values on concentration that corresponded to the weak self-association of FH. Global sedimentation equilibrium fits indicated that a monomer-dimer equilibrium best described the data up to 1.3 mg/ml with a fitted dissociation constant K-D of 28 mu M and that higher oligomers formed at increased concentrations. The KD showed that about 85-95% of serum FH will be monomeric in the absence of other factors. Size-distribution analyses in sedimentation velocity experiments showed that monomeric FH was the major species but that as many as six oligomeric forms co-existed with it. The data were explained in terms of two weak dimerisation sites recently identified in the SCR-6/8 and SCR-16/20 fragments of FH with similar KD values. These observations indicate a mechanism for the progressive self-association of FH and may be relevant for complement regulation and the formation of drusen deposits that are associated with age-related macular degeneration. (c) 2007 Elsevier Ltd. All rights reserved.
机译：因子H（FH）是补体替代途径激活的主要调节剂。它由20个短补体调节子（SCR）域组成，并在遗传上关联为与年龄相关的黄斑变性的危险因素。先前对FH的研究表明，它以单体和二聚体形式存在。改进的野生型FH的X射线散射和分析超速离心方法使这些低聚物的性质得以澄清。较低浓度下的数据表明，X射线旋转半径值对浓度的依赖性与FH的弱自缔合相对应。总体沉降平衡拟合表明，单体-二聚体平衡最能描述数据高达1.3 mg / ml，拟合的解离常数K-D为28μM，并且较高的低聚物在增加的浓度下形成。 KD表明，在没有其他因素的情况下，约85-95％的血清FH将是单体的。沉降速度实验中的尺寸分布分析表明，单体FH是主要种类，但同时存在多达6种寡聚形式。根据最近在具有相似KD值的FH的SCR-6 / 8和SCR-16 / 20片段中发现的两个弱二聚位点来解释数据。这些观察结果表明FH进行性自我缔合的机制，可能与补体调节和与年龄相关的黄斑变性相关的玻璃疣沉积物的形成有关。 （c）2007 Elsevier Ltd.保留所有权利。

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