Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains
Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains
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DOI：
10.1038/nature07254
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发表时间：
2008-09-18
期刊：
影响因子：
64.8
通讯作者：
Fukai, Shuya
中科院分区：
文献类型：
--
作者：
Sato, Yusuke;Yoshikawa, Azusa;Fukai, Shuya
去泛素化酶（DUBs）从结合底物中去除泛素以调节各种细胞过程。Zn 2+依赖性DUBs AMSH和AMSH-LP通过特异性切割来自内化受体的Lys 63连接的多聚泛素链来调节受体运输。在这里，我们报告的晶体结构的人AMSH-LP DUB结构域单独和在复杂的Lys 63连接的二泛素在1.2埃和1.6埃分辨率分别。AMSH-LP DUB结构域由一个Zn 2+配位催化核心和两个特征性插入物Ins- 1和Ins- 2组成。远端泛素与Ins- 1和核心相互作用，而近端泛素与Ins- 2和核心相互作用。核心和Ins- 1形成一个催化沟，容纳近端泛素的Lys 63侧链和远端泛素的异肽连接的羧基末端尾.这是第一个报道的DUB与异肽连接的泛素链复合的结构，揭示了AMSH家族成员对Lys 63连接特异性去泛素化的机制。
Deubiquitinating enzymes ( DUBs) remove ubiquitin from conjugated substrates to regulate various cellular processes. The Zn2+-dependent DUBs AMSH and AMSH- LP regulate receptor trafficking by specifically cleaving Lys 63- linked polyubiquitin chains from internalized receptors. Here we report the crystal structures of the human AMSH- LP DUB domain alone and in complex with a Lys 63- linked di- ubiquitin at 1.2 angstrom and 1.6 angstrom resolutions, respectively. The AMSH- LP DUB domain consists of a Zn2+-coordinating catalytic core and two characteristic insertions, Ins- 1 and Ins- 2. The distal ubiquitin interacts with Ins- 1 and the core, whereas the proximal ubiquitin interacts with Ins- 2 and the core. The core and Ins- 1 form a catalytic groove that accommodates the Lys 63 side chain of the proximal ubiquitin and the isopeptide- linked carboxy- terminal tail of the distal ubiquitin. This is the first reported structure of a DUB in complex with an isopeptide- linked ubiquitin chain, which reveals the mechanism for Lys 63- linkage- specific deubiquitination by AMSH family members.