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Crystal structure of the human COP9 signalosome

机译：人COP9信号小体的晶体结构

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摘要

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 Zn~(2+)-dependent isopeptidase that is inactive in isolation. Here we present the crystal structure of the entire ～350-kDa human CSN holoenzyme at 3.8 A resolution, detailing the molecular architecture of the complex. CSN has two organizational centres: a horseshoe-shaped ring created by its sixproteasomelid-CSN-initiation factor 3 (PCI) domain proteins, and a large bundle formed by the carboxy-terminal a-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.
机译：泛素化是至关重要的细胞信号传导过程，并在多个级别上受到控制。 Cullin-RING E3泛素连接酶（CRL）受COP9信号亚体的8个亚基（CSN）调控。 CSN通过去除其共价连接的活化剂NEDD8来使CRL失活。 CSN对NEDD8的切割被CSN5催化，CSN5是一种依赖Zn〜（2+）的异肽酶，在分离中没有活性。在这里，我们以3.8 A的分辨率呈现了整个〜350 kDa人类CSN全酶的晶体结构，详述了该复合物的分子结构。 CSN具有两个组织中心：由其六个蛋白酶体-CSN起始因子3（PCI）域蛋白产生的马蹄形环，以及由每个亚基的羧基末端a-螺旋形成的大束。 CSN5及其二聚合作伙伴CSN6复杂地嵌入了螺旋束的核心。在无底物的全酶中，CSN5是自动抑制的，因此无法进入活性位点。我们发现，CSN4可以检测到与CSN结合的NCR，并在CSN6的帮助下与CSN5进行通讯，从而激活树突化酶。

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  • 来源
    《Nature》 |2014年第7513期|161-165|共5页
  • 作者

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

  • 作者单位

    Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66,4058 Basel, Switzerland,University of Basel, Petersplatz 10,4003 Basel, Switzerland;

    Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66,4058 Basel, Switzerland,University of Basel, Petersplatz 10,4003 Basel, Switzerland;

    Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66,4058 Basel, Switzerland,University of Basel, Petersplatz 10,4003 Basel, Switzerland;

    Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66,4058 Basel, Switzerland;

    Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, 4056 Basel, Switzerland;

    Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, 4056 Basel, Switzerland;

    Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66,4058 Basel, Switzerland,University of Basel, Petersplatz 10,4003 Basel, Switzerland;

    Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66,4058 Basel, Switzerland,University of Basel, Petersplatz 10,4003 Basel, Switzerland;

  • 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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