Mechanism of phosphoribosyl-ubiquitination mediated by a single Legionella effector.
Mechanism of phosphoribosyl-ubiquitination mediated by a single Legionella effector.
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DOI：
10.1038/s41586-018-0147-6
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发表时间：
2018-05
期刊：
影响因子：
64.8
通讯作者：
Mao Y
中科院分区：
文献类型：
--
作者：
Akturk A;Wasilko DJ;Wu X;Liu Y;Zhang Y;Qiu J;Luo ZQ;Reiter KH;Brzovic PS;Klevit RE;Mao Y
泛素化是一种翻译后修饰，在真核生物中调节无数的细胞过程。传统的泛素化级联反应在泛素（Ub）的C-末端和靶蛋白之间的共价连接中达到高潮，最常见的是在赖氨酸侧链上。嗜肺军团菌SidE家族效应蛋白的最新研究揭示了一种新的泛素化模式，其中磷酸核糖基化的泛素（PR-Ub）通过磷酸二酯键与底物上的丝氨酸残基缀合。为了揭示这种独特的翻译后修饰的分子机制，我们确定了保留泛素化活性的SidE家族成员SdeA片段的晶体结构。结构表明，催化模块包含两个不同的功能单元：磷酸二酯酶结构域（PDE）和单ADP核糖基转移酶（mART）结构域。生化分析表明，mART结构域介导的Ub转化为ADP-核糖基化Ub（ADPR-Ub）和PDE结构域介导的PR-Ub与底物的连接是SdeA的两个独立活性。此外，我们提出了两个晶体结构的同源PDE域从SidE家族成员SdeD在复杂的Ub或ADPR-Ub。这些结构表明了SdeA如何将ADPR-Ub加工成PR-Ub加AMP并将PR-Ub与底物中的丝氨酸残基缀合的有趣机制。我们的研究建立了磷酸核糖泛素化（PR-泛素化）的分子机制，并为真核生物中这种不寻常的泛素化类型的未来研究铺平了道路。
Ubiquitination is a post-translational modification that regulates a myriad of cellular processes in eukaryotes. The conventional ubiquitination cascade culminates in a covalent linkage between the C-terminus of ubiquitin (Ub) and a target protein, most often on a lysine sidechain. Recent studies of the Legionella pneumophila SidE family of effector proteins revealed a novel mode of ubiquitination in which a phosphoribosylated ubiquitin (PR-Ub) is conjugated to a serine residue on substrates via a phosphodiester bond. To uncover the molecular mechanism of this unique post-translational modification, we determined the crystal structure of a fragment of the SidE family member SdeA that retains ubiquitination activity. The structure reveals that the catalytic module contains two distinct functional units: a phosphodiesterase domain (PDE) and a mono-ADP-ribosyltransferase (mART) domain. Biochemical analysis shows that the mART domain-mediated conversion of Ub to ADP-ribosylated Ub (ADPR-Ub) and the PDE domain-mediated ligation of PR-Ub to substrates are two independent activities of SdeA. Furthermore, we present two crystal structures of a homologous PDE domain from the SidE family member SdeD in complex with Ub or ADPR-Ub. The structures suggest an intriguing mechanism for how SdeA processes ADPR-Ub to PR-Ub plus AMP and conjugates PR-Ub to a serine residue in substrates. Our study establishes the molecular mechanism of phosphoribosyl-ubiquitination (PR-ubiquitination) and paves the way for future studies of this unusual type of ubiquitination in eukaryotes.
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影响因子：
30.3
作者：
Kotewicz KM;Ramabhadran V;Sjoblom N;Vogel JP;Haenssler E;Zhang M;Behringer J;Scheck RA;Isberg RR
通讯作者：
Isberg RR
影响因子：
6.7
作者：
Luo X;Wasilko DJ;Liu Y;Sun J;Wu X;Luo ZQ;Mao Y
通讯作者：
Mao Y
影响因子：
64.8
作者：
Kalayil S;Bhogaraju S;Bonn F;Shin D;Liu Y;Gan N;Basquin J;Grumati P;Luo ZQ;Dikic I
通讯作者：
Dikic I
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：
12.4
作者：
Hurley JH;Stenmark H
通讯作者：
Stenmark H