Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement
Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement
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DOI：
10.1073/pnas.1017087108
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发表时间：
2011-02-15
影响因子：
11.1
通讯作者：
Jokiranta, T. Sakari
中科院分区：
文献类型：
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作者：
Kajander, Tommi;Lehtinen, Markus J.;Jokiranta, T. Sakari
补体的旁路途径在先天免疫中很重要，不仅攻击微生物，而且通过强大的扩增攻击所有未受保护的生物表面。宿主和非宿主表面如何在分子水平上区分尚不清楚，但关键组分是补体调节因子H（FH）的结构域19-20，其与宿主相互作用（即，非活化剂表面糖胺聚糖或唾液酸）和C3 b的C3 d部分。我们在2.3埃分辨率下的FH 19 -20：C3 d复合物的结构表明，FH 19 -20具有两个不同的C3 b结合位点，FH 19和FH 20。我们显示了FH 19与C3 b和FH 20与非活化剂表面糖胺聚糖的同时结合，并且我们表明这两种相互作用对于FH与非活化剂表面上的C3 b的完全结合是必需的（即，目标识别）。我们还表明，C3 d可以取代糖胺聚糖结合FH 20，从而提供了一个反馈控制，以防止过量的C3 b沉积和补体扩增。这解释了非典型溶血性尿毒症综合征的分子基础，其中FH 19 -20和C3 d之间或FH 20和糖胺聚糖之间的结合界面上的突变导致补体攻击宿主表面。
The alternative pathway of complement is important in innate immunity, attacking not only microbes but all unprotected biological surfaces through powerful amplification. It is unresolved how host and nonhost surfaces are distinguished at the molecular level, but key components are domains 19-20 of the complement regulator factor H (FH), which interact with host (i.e., nonactivator surface glycosaminoglycans or sialic acids) and the C3d part of C3b. Our structure of the FH19-20:C3d complex at 2.3-angstrom resolution shows that FH19-20 has two distinct binding sites, FH19 and FH20, for C3b. We show simultaneous binding of FH19 to C3b and FH20 to nonactivator surface glycosaminoglycans, and we show that both of these interactions are necessary for full binding of FH to C3b on nonactivator surfaces (i.e., for target discrimination). We also show that C3d could replace glycosaminoglycan binding to FH20, thus providing a feedback control for preventing excess C3b deposition and complement amplification. This explains the molecular basis of atypical hemolytic uremic syndrome, where mutations on the binding interfaces between FH19-20 and C3d or between FH20 and glycosaminoglycans lead to complement attack against host surfaces.