Jokiranta T Sakari, Jaakola Veli-Pekka, Lehtinen Markus J, Pärepalo Maria, Meri Seppo, Goldman Adrian
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland.
EMBO J. 2006 Apr 19;25(8):1784-94. doi: 10.1038/sj.emboj.7601052. Epub 2006 Apr 6.
Factor H (FH) is the key regulator of the alternative pathway of complement. The carboxyl-terminal domains 19-20 of FH interact with the major opsonin C3b, glycosaminoglycans, and endothelial cells. Mutations within this area are associated with atypical haemolytic uremic syndrome (aHUS), a disease characterized by damage to endothelial cells, erythrocytes, and kidney glomeruli. The structure of recombinant FH19-20, solved at 1.8 A by X-ray crystallography, reveals that the short consensus repeat domain 20 contains, unusually, a short alpha-helix, and a patch of basic residues at its base. Most aHUS-associated mutations either destabilize the structure or cluster in a unique region on the surface of FH20. This region is close to, but distinct from, the primary heparin-binding patch of basic residues. By mutating five residues in this region, we show that it is involved, not in heparin, but in C3b binding. Therefore, the majority of the aHUS-associated mutations on the surface of FH19-20 interfere with the interaction between FH and C3b. This obviously leads to impaired control of complement attack on plasma-exposed cell surfaces in aHUS.
补体因子H（FH）是补体替代途径的关键调节因子。FH的羧基末端结构域19-20与主要调理素C3b、糖胺聚糖和内皮细胞相互作用。该区域内的突变与非典型溶血性尿毒症综合征（aHUS）相关，这是一种以内皮细胞、红细胞和肾小球受损为特征的疾病。通过X射线晶体学在1.8埃分辨率下解析的重组FH19-20的结构显示，短共有重复序列结构域20异常地包含一个短α螺旋及其底部的一片碱性残基。大多数与aHUS相关的突变要么使结构不稳定，要么聚集在FH20表面的一个独特区域。该区域靠近但不同于主要的碱性残基肝素结合区。通过在该区域突变五个残基，我们表明它参与的不是肝素结合，而是C3b结合。因此，FH19-20表面上大多数与aHUS相关的突变会干扰FH与C3b之间的相互作用。这显然导致aHUS中对血浆暴露细胞表面的补体攻击控制受损。
