Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System
Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System
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DOI：
10.3389/fimmu.2019.02007
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发表时间：
2019-08-22
影响因子：
7.3
通讯作者：
Andersen, Gregers R.
中科院分区：
文献类型：
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作者：
Pedersen, Dennis V.;Gadeberg, Trine A. F.;Andersen, Gregers R.
备解素（FP）是免疫系统的正调节剂，其刺激补体系统的旁路途径中具有蛋白水解活性的C3转化酶C3 bBb的活性。在这里，我们给出了FP的两种晶体结构和转化酶结合FP的两种结构。由三个血小板反应蛋白重复序列（TSR）和TB结构域形成的结构核心含有FP中主要与C3 b相互作用的转化酶结合位点。建议通过FP TSR 5稳定Bb蛋白酶中C3 b C-末端和MIDAS结合的Mg 2+之间的相互作用是FP转化酶稳定的基础。FP和转化酶亚基的结构建议之间的分子间接触的结合实验证实。FP显示出由于对C3 b上的共同结合位点的直接竞争而抑制Fl对C3 b的降解。FP寡聚体通过两组分子间接触保持在一起，其中第一组由来自一个FP分子的TB结构域和来自另一个FP分子的TSR 4形成。第二个也是最大的界面由来自相同的两个FP分子的TSR 1和TSR 6形成。血小板反应蛋白重复之间的四个铰链的灵活性，建议使低聚，多分散，和扩展架构的FP。我们的结构合理化与FP缺陷相关的突变的影响，并提供了一个结构基础的FP功能的分析，在转换酶及其可能的作用，在模式识别。
Properdin (FP) is a positive regulator of the immune system stimulating the activity of the proteolytically active C3 convertase C3bBb in the alternative pathway of the complement system. Here we present two crystal structures of FP and two structures of convertase bound FP. A structural core formed by three thrombospondin repeats (TSRs) and a TB domain harbors the convertase binding site in FP that mainly interacts with C3b. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg2+ in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. FP is shown to inhibit C3b degradation by Fl due to a direct competition for a common binding site on C3b. FP oligomers are held together by two sets of intermolecular contacts, where the first is formed by the TB domain from one FP molecule and TSR4 from another. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. Our structures rationalize the effects of mutations associated with FP deficiencies and provide a structural basis for the analysis of FP function in convertases and its possible role in pattern recognition.