Implications of the progressive self-association of wild-type human factor H6 for complement regulation and disease
Implications of the progressive self-association of wild-type human factor H6 for complement regulation and disease
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DOI：
10.1016/j.jmb.2007.11.015
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发表时间：
2008-01-25
影响因子：
5.6
通讯作者：
Perkins, Stephen J.
中科院分区：
文献类型：
--
作者：
Nan, Ruodan;Gor, Jayesh;Perkins, Stephen J.
因子H（FH）是补体旁路途径活化的主要调节剂。它由20个短补体调节因子（SCR）结构域组成，在遗传上与年龄相关性黄斑变性的风险因素相关。以往的研究表明FH以单体和二聚体形式存在。改进的X-射线散射和分析ultracentragation野生型FH的方法允许澄清这些低聚物的性质。在较低的浓度下的数据显示的依赖性的X-射线的回转半径值的浓度，对应于弱的自关联FH。全球沉降平衡拟合表明，单体-二聚体平衡最好地描述了高达1.3毫克/毫升的数据，拟合解离常数K-D为28 μ M，并且在增加的浓度下形成更高的低聚物。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是主要的物种，但多达6个寡聚体的形式与it. The数据解释在两个弱的二聚化位点最近确定的SCR-6/8和SCR-16/20片段FH具有相似的KD值。这些观察结果表明FH的进行性自相关机制，可能与补体调节和与年龄相关性黄斑变性相关的玻璃疣沉积物的形成有关。(c)2007爱思唯尔有限公司保留所有权利。
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.