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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural basis for activation of the complement system by component C4 cleavage
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Structural basis for activation of the complement system by component C4 cleavage

机译：通过组分C4裂解激活补体系统的结构基础

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摘要

An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4MASP-2 substrate-enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 A from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C-CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme-substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen-antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.
机译：先天性免疫的一个重要方面是通过凝集素和经典途径（补体系统的三个成熟的激活途径中的两个）识别病原体表面或自身改变的分子模式。这种识别引起MASP-2或C1s丝氨酸蛋白酶的激活，然后裂解蛋白C4。在这里，我们介绍了203 kDa人类C4和245 kDa C4MASP-2底物酶复合物的晶体结构。当C4与MASP-2结合时，会诱导C4发生构象变化，其易裂键区变得有序，并以丝氨酸蛋白酶的典型方式插入蛋白酶催化位点。在MASP-2中，位于CCP域内的异位点可从易断裂键识别C4 C345C域60A。 C345C-CCP界面处C4和MASP-2残基的突变抑制了分子​​间相互作用和C4裂解。讨论了由聚糖结合的甘露聚糖结合凝集素，MASP-2和C4组成的巨大体内酶-底物复合物的可能组装。我们自己和先前的功能数据表明，经典补体途径中的C1（例如由抗原-抗体复合物激活）还通过CCP外位点识别C4 C345C结构域。我们的结果提供了一个统一的结构框架，用于了解C4裂解在消除病原体和通过补体激活的两种主要途径改变自身的过程中所必需的早期步骤。

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    Rune T. Kidmose; Nick S. Laursen; Jozsef Dobo; Troels R. Kjaer; Sofia Sirotkina; Laure Yatime; Lars Sottrup-Jensen; Steffen Thiel; Peter Gal; Gregers R. Andersen;

  • 作者单位

    Departments of Molecular Biology and Genetics Aarhus University, DK-8000 Aarhus, Denmark;

    Departments of Molecular Biology and Genetics Aarhus University, DK-8000 Aarhus, Denmark;

    Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1113, Budapest, Hungary;

    Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark;

    Departments of Molecular Biology and Genetics Aarhus University, DK-8000 Aarhus, Denmark;

    Departments of Molecular Biology and Genetics Aarhus University, DK-8000 Aarhus, Denmark;

    Departments of Molecular Biology and Genetics Aarhus University, DK-8000 Aarhus, Denmark;

    Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark;

    Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1113, Budapest, Hungary;

    Departments of Molecular Biology and Genetics Aarhus University, DK-8000 Aarhus, Denmark;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    crystallography; pattern recognition; proteolysis; structural biology;

    机译：晶体学模式识别;蛋白水解结构生物学;

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