The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome.
The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome.
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DOI：
10.4049/jimmunol.0804031
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发表时间：
2009-06-01
期刊：
影响因子：
--
通讯作者：
Kavanagh D
中科院分区：
文献类型：
--
作者：
Ferreira VP;Herbert AP;Cortés C;McKee KA;Blaum BS;Esswein ST;Uhrín D;Barlow PN;Pangburn MK;Kavanagh D
因子H（fH）对于液相和表面上的补体稳态是必需的。它的两个C-末端结构域（CCP 19-20）锚fH至自身表面，在那里它防止在需要其N-末端四个结构域的过程中的C3 b扩增。在非典型溶血性尿毒综合征（阿胡斯）中，fH的C-末端聚集的突变可能会破坏与表面相关的C3 b或聚阴离子的相互作用，从而降低fH调节补体的能力。为了测试这一点，我们比较了包含CCP 19-20的重组蛋白与16个突变体。这些突变对蛋白质结构的影响非常有限和局部化。虽然我们发现了四个aHUS相关的fH突变，减少了与C3 b和/或肝素（细胞表面聚阴离子碳水化合物的模型化合物）的结合，但我们鉴定了五个aHUS相关的突变体，其对任一种或两种配体的亲和力增加。引人注目的是，这些对单个配体的可变亲和力与所有aHUS相关突变体在更生理学的测定中被发现受损的程度无关，所述测定测量它们抑制全长fH的细胞表面补体功能的能力。总而言之，我们的数据表明，复杂的fH自身表面识别过程（涉及蛋白质和生理碳水化合物配体亲和力的平衡）的破坏容易导致阿胡斯。
Factor H (fH) is essential for complement homeostasis in fluid-phase and on surfaces. Its two C-terminal domains (CCP 19-20) anchor fH to self surfaces where it prevents C3b amplification in a process requiring its N-terminal four domains. In atypical hemolytic uremic syndrome (aHUS), mutations clustering towards the C-terminus of fH may disrupt interactions with surface-associated C3b or polyanions and thereby diminish the ability of fH to regulate complement. To test this we compared a recombinant protein encompassing CCP 19-20 with sixteen mutants. The mutations had only very limited and localized effects on protein structure. While we found four aHUS-linked fH mutations that decreased binding to C3b and/or to heparin (a model compound for cell-surface polyanionic carbohydrates), we identified five aHUS-associated mutants with increased affinity for either or both ligands. Strikingly, these variable affinities for the individual ligands did not correlate with the extent to which all the aHUS-associated mutants were found to be impaired in a more physiological assay that measured their ability to inhibit cell surface complement functions of full-length fH. Taken together, our data suggest that disruption of a complex fH-self surface recognition process, involving a balance of affinities for protein and physiological carbohydrate ligands, predisposes to aHUS.
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