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封面故事:人“COP9 信号小体” 的晶体结构

摘要 : 瑞士弗雷德里希·米歇尔生物医学研究所、巴塞尔大学和诺华制药公司合作,解析“COP9 信号小体” 的分辨率为3.8 Å 的晶体结构,揭示该复合物是怎样做到对其基质具有如此精妙特异性的。相关文章发表于2014年7月16日的《Nature》杂志上。


“COP9 信号小体” (CSN)是一个大型蛋白复合物,在泛素-蛋白酶体细胞内蛋白降解通道中发挥功能。它是20年前在发育中的拟南芥苗中首次被发现的,现在被认为是所有动物、植物和真菌的调控机制的构成部分。

在这篇文章中,Nicolas Thomä及同事发表了由8个亚单元组成的整个人“COP9 信号小体” 的分辨率为3.8 Å 的晶体结构,从而为了解其分子架构和作用机制提供了信息。该结构显示了这一复合物是怎样做到对其基质具有如此精妙特异性的。


Crystal structure of the human COP9 signalosome

Gondichatnahalli M. Lingaraju, Richard D. Bunker, Simone Cavadini, Daniel Hess, Ulrich Hassiepen, Martin Renatus, Eric S. Fischer & Nicolas H. Thomä

Ubiquitination is a crucial cellular signalling process, and is controlled on multiple levels. Cullin–RING E3 ubiquitin ligases (CRLs) are regulated by the eight-subunit COP9 signalosome (CSN). CSN inactivates CRLs by removing their covalently attached activator, NEDD8. NEDD8 cleavage by CSN is catalysed by CSN5, a Zn2+-dependent isopeptidase that is inactive in isolation. Here we present the crystal structure of the entire ~350-kDa human CSN holoenzyme at 3.8 Å resolution, detailing the molecular architecture of the complex. CSN has two organizational centres: a horseshoe-shaped ring created by its six proteasome lid–CSN–initiation factor 3 (PCI) domain proteins, and a large bundle formed by the carboxy-terminal α-helices of every subunit. CSN5 and its dimerization partner, CSN6, are intricately embedded at the core of the helical bundle. In the substrate-free holoenzyme, CSN5 is autoinhibited, which precludes access to the active site. We find that neddylated CRL binding to CSN is sensed by CSN4, and communicated to CSN5 with the assistance of CSN6, resulting in activation of the deneddylase.

对应Nature杂志: 2014年8月14日Nature杂志精选

来源: Nature 浏览次数:157


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