Dimerization of complement factor H-related proteins modulates complement activation in vivo
Dimerization of complement factor H-related proteins modulates complement activation in vivo
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DOI：
10.1073/pnas.1219260110
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发表时间：
2013-03-19
影响因子：
11.1
通讯作者：
Lea, Susan M.
中科院分区：
文献类型：
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作者：
de Jorge, Elena Goicoechea;Caesar, Joseph J. E.;Lea, Susan M.
补体系统是影响老年性黄斑变性、脑膜炎和肾脏疾病易感性的关键成分。变异包括补体因子H相关(CFHR)基因座内的基因组重排。由于缺乏对CFHR蛋白生物学作用的了解，阐明这些关联的机制一直受到阻碍。在这里，我们提供了独特的结构数据，证明了三个CFHR蛋白包含一个共同的二聚化基序，并且这一迄今未被识别的结构特性使同源二聚体和异源二聚体的形成成为可能。二聚化使组织结合的补体片段具有亲和力，并使这些蛋白质能够有效地与生理性补体抑制因子H(CFH)竞争配体结合。我们的数据表明，这些CFHR蛋白作为CFH的竞争性拮抗剂在体内调节补体激活，并解释了为什么CFHR的变异容易导致疾病。
The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related (CFHR) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.