Divergence in Ubiquitin Interaction and Catalysis among the Ubiquitin-Specific Protease Family Deubiquitinating Enzymes.
Divergence in Ubiquitin Interaction and Catalysis among the Ubiquitin-Specific Protease Family Deubiquitinating Enzymes.
复制标题
泛素特异性蛋白酶家族去泛素化酶之间泛素相互作用和催化作用的差异。
DOI：
10.1021/acs.biochem.6b00033
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发表时间：
2016
期刊：
影响因子：
2.9
通讯作者：
Zhuang,Zhihao
中科院分区：
文献类型：
--
作者：
Tencer,AdamH;Liang,Qin;Zhuang,Zhihao
去遍在蛋白酶（DUB）负责逆转蛋白质的单遍在蛋白质和多遍在蛋白质的单遍在蛋白质和多遍在蛋白质的多遍在蛋白质的多遍已经鉴定了近100种人DUB，并将其分为五个家族，其中泛素特异性蛋白酶（USP）家族是最大的（>50个成员）。泛素（Ub）与USP的结合与泛素C-末端水解酶（UCH）和卵巢肿瘤结构域蛋白酶（OTU）家族中DUB的结合明显不同。我们产生了一组突变的泛素，并用它们来探测泛素与一些USP的相互作用。我们的研究结果揭示了一个显着的分歧的USP-Ub之间的相互作用的USP催化域。我们的双突变体循环分析靶向位于泛素的尖端，中心体和尾部的泛素残基也证明了USP-Ub相互作用之间的不同串扰。这项工作揭示了USP家族DUB中泛素结合模式的有趣差异，并提出了通过小分子拮抗剂靶向USP上的泛素结合热点以选择性抑制USP的可能性。
Deubiquitinating enzymes (DUBs) are responsible for reversing mono- and polyubiquitination of proteins and play essential roles in numerous cellular processes. Close to 100 human DUBs have been identified and are classified into five families, with the ubiquitin-specific protease (USP) family being the largest (>50 members). The binding of ubiquitin (Ub) to USP is strikingly different from that observed for the DUBs in the ubiquitin C-terminal hydrolase (UCH) and ovarian tumor domain protease (OTU) families. We generated a panel of mutant ubiquitins and used them to probe the ubiquitin’s interaction with a number of USPs. Our results revealed a remarkable divergence of USP–Ub interactions among the USP catalytic domains. Our double-mutant cycle analysis targeting the ubiquitin residues located in the tip, the central body, and the tail of ubiquitin also demonstrated different crosstalk among the USP–Ub interactions. This work uncovered intriguing divergence in the ubiquitin-binding mode in the USP family DUBs and raised the possibility of targeting the ubiquitin-binding hot spots on USPs for selective inhibition of USPs by small molecule antagonists.