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Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I

机译：RIG-I激活泛素介导的抗病毒信号的结构基础

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摘要

Ubiquitin (Ub) has important roles in a wide range of intracellular signalling pathways. In the conventional view, ubiquitin alters the signalling activity of the target protein through covalent modification, but accumulating evidence points to the emerging role of non-covalent interaction between ubiquitin and the target. In the innate immune signalling pathway of a viral RNA sensor, RIG-I, both covalent and non-covalent interactions with K63-linked ubiquitin chains (K63-Ub_n) were shown to occur in its signalling domain, a tandem caspase activation and recruitment domain (hereafter referred to as 2CARD). Non-covalent binding of K63-Ub_n to 2CARD induces its tetramer formation, a requirement for downstream signal activation. Here we report the crystal structure of the tetramer of human RIG-I 2CARD bound by three chains of K63-Ub_2. 2CARD assembles into a helical tetramer resembling a 'lock-washer', in which the tetrameric surface serves as a signalling platform for recruitment and activation of the downstream signalling molecule, MAVS. Ubiquitin chains are bound along the outer rim of the helical trajectory, bridging adjacent subunits of 2CARD and stabilizing the 2CARD tetramer. The combination of structural and functional analyses reveals that binding avidity dictates the K63-linkage and chain-length specificity of 2CARD, and that covalent ubiquitin conjugation of 2CARD further stabilizes the Ub-2CARD interaction and thus the 2CARD tetramer. Our work provides unique insights into the novel types of ubiquitin mediated signal-activation mechanism, and previously unexpected synergism between the covalent and non-covalent ubiquitin interaction modes.
机译：泛素（Ubquitin）（Ub）在广泛的细胞内信号传导途径中具有重要作用。按照常规观点，泛素通过共价修饰改变靶蛋白的信号传导活性，但是越来越多的证据表明泛素和靶标之间非共价相互作用的新兴作用。在病毒RNA传感器RIG-I的固有免疫信号传导途径中，与K63连接的泛素链（K63-Ub_n）的共价和非共价相互作用均显示在其信号传导域，串联半胱天冬酶激活和募集域中（以下称为2CARD）。 K63-Ub_n与2CARD的非共价结合会诱导其四聚体形成，这是下游信号激活的必要条件。在这里，我们报告人类的RIG-1 2CARD四聚体的晶体结构被三链的K63-Ub_2绑定。 2CARD组装成类似于“锁紧垫圈”的螺旋四聚体，其中四聚体表面充当用于募集和激活下游信号分子MAVS的信号平台。遍在蛋白链沿螺旋轨迹的外缘结合，桥接2CARD的相邻亚基并稳定2CARD四聚体。结构和功能分析的结合表明，结合亲和力决定了2CARD的K63连接和链长特异性，而2CARD的共价泛素结合进一步稳定了Ub-2CARD相互作用，从而稳定了2CARD四聚体。我们的工作提供了对新型泛素介导的信号激活机制以及共价和非共价泛素相互作用模式之间出乎意料的协同作用的独特见解。

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  • 来源
    《Nature》 |2014年第7498期|110-114|共5页
  • 作者

    Alys Peisley; Bin Wu; Hui Xu; Zhijian J. Chen; Sun Hur;

  • 作者单位

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 USA ,Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA;

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 USA ,Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA;

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA ,Howard Hughes Medical Institute Chevy Chase Maryland 20815, USA;

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 USA ,Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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