Structural basis of ubiquitin modification by the Legionella effector SdeA
Structural basis of ubiquitin modification by the Legionella effector SdeA
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军团菌效应子 SdeA 泛素修饰的结构基础
DOI：
10.1038/s41586-018-0146-7
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发表时间：
2018-05-31
期刊：
影响因子：
64.8
通讯作者：
Feng, Yue
中科院分区：
文献类型：
--
作者：
Dong, Yanan;Mu, Yajuan;Feng, Yue
蛋白质泛素化是一种多方面的翻译后修饰，几乎控制着真核细胞中的每一个过程。最近，军团菌效应子SdeA被报道通过其单ADP核糖基转移酶（mART）和磷酸二酯酶（PDE）结构域连续修饰泛素（Ub）的Arg 42介导独特的磷酸核糖基连接的泛素化。然而，SdeA介导的Ub修饰和磷酸核糖连接的泛素化的机制仍然未知。在这里，我们报告的SdeA在其配体自由，Ub结合和Ub-NADH结合状态的结构。结构表明，SdeA的mART和PDE结构域在其C-末端区域形成催化结构域。在Ub结合后，SdeA的mART结构域中的经典ADP-核糖基转移酶毒素转角（ARTT）和磷酸盐-烟酰胺（PN）环发生显著的构象变化。Ub的Arg 72可能作为“探针”，首先与mART结构域相互作用，然后在Ub的ADP-核糖基化过程中，Arg 72和Arg 42的侧链可能发生移动。我们的研究揭示了SdeA介导的Ub修饰的机制，并为进一步研究磷酸核糖基连接的泛素化过程提供了框架。军团菌效应子SdeA在无配体状态下以及与泛素和NADH复合的晶体结构提供了对SdeA介导的磷酸核糖基连接的泛素化的深入了解。
Protein ubiquitination is a multifaceted post-translational modification that controls almost every process in eukaryotic cells. Recently, the Legionella effector SdeA was reported to mediate a unique phosphoribosyl-linked ubiquitination through successive modifications of the Arg42 of ubiquitin (Ub) by its mono-ADP-ribosyltransferase (mART) and phosphodiesterase (PDE) domains. However, the mechanisms of SdeA-mediated Ub modification and phosphoribosyl-linked ubiquitination remain unknown. Here we report the structures of SdeA in its ligand-free, Ub-bound and Ub–NADH-bound states. The structures reveal that the mART and PDE domains of SdeA form a catalytic domain over its C-terminal region. Upon Ub binding, the canonical ADP-ribosyltransferase toxin turn-turn (ARTT) and phosphate-nicotinamide (PN) loops in the mART domain of SdeA undergo marked conformational changes. The Ub Arg72 might act as a ‘probe’ that interacts with the mART domain first, and then movements may occur in the side chains of Arg72 and Arg42 during the ADP-ribosylation of Ub. Our study reveals the mechanism of SdeA-mediated Ub modification and provides a framework for further investigations into the phosphoribosyl-linked ubiquitination process. Crystal structures of the Legionella effector SdeA in a ligand-free state and in complex with ubiquitin and NADH provide insight into SdeA-mediated phosphoribosyl-linked ubiquitination.