Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I.
Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I.
复制标题
DOI：
10.1038/nature13140
复制
发表时间：
2014-05-01
期刊：
影响因子：
64.8
通讯作者：
Hur S
中科院分区：
文献类型：
--
作者：
Peisley A;Wu B;Xu H;Chen ZJ;Hur S
泛素 (Ub) 在多种细胞内信号传导通路中发挥重要作用。传统观点认为，泛素通过共价修饰改变靶蛋白的信号传导活性，但越来越多的证据表明泛素与靶标之间非共价相互作用的作用正在显现。在病毒 RNA 传感器 RIG-I 的先天免疫信号通路中，与 K63 连接的泛素链 (K63-Ubn) 的共价和非共价相互作用均发生在其信号结构域、串联 caspase 激活和募集结构域（以下称为 2CARD）中。 K63-Ubn 与 2CARD 的非共价结合诱导其四聚体形成，这是下游信号激活的必要条件。在这里，我们报道了由 K63-Ub2 的三个链结合的人 RIG-I 2CARD 四聚体的晶体结构。 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下游信号分子 MAVS 的招募和激活的信号平台。泛素链沿着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，并且 2CARD 的共价泛素缀合进一步稳定了 Ub-2CARD 相互作用，从而稳定了 2CARD 四聚体。我们的工作为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意想不到的协同作用提供了独特的见解。
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-Ubn) 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-Ubn 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-Ub2. 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.
登录
查看更多内容
影响因子：
64.8
作者：
Jiang, Fuguo;Ramanathan, Anand;Miller, Matthew T.;Tang, Guo-Qing;Gale, Michael, Jr.;Patel, Smita S.;Marcotrigiano, Joseph
通讯作者：
Marcotrigiano, Joseph
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Zeng W;Sun L;Jiang X;Chen X;Hou F;Adhikari A;Xu M;Chen ZJ
通讯作者：
Chen ZJ
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
30.5
作者：
Kawai, T;Takahashi, K;Akira, S
通讯作者：
Akira, S