Mechanism of USP7/HAUSP Activation by Its C-Terminal Ubiquitin-like Domain and Allosteric Regulation by GMP-Synthetase
Mechanism of USP7/HAUSP Activation by Its C-Terminal Ubiquitin-like Domain and Allosteric Regulation by GMP-Synthetase
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DOI：
10.1016/j.molcel.2011.06.034
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发表时间：
2011-10-07
期刊：
影响因子：
16
通讯作者：
Sixma, Titia K.
中科院分区：
文献类型：
--
作者：
Faesen, Alex C.;Dirac, Annette M. G.;Sixma, Titia K.
泛素特异性蛋白酶USP7/HAUSP调节p53和MDM2水平，以及FOXO4和PTEN的细胞定位，因此对它们在细胞过程中的作用至关重要。在这里，我们展示了USP7的64 kDa c端区域如何积极调节去泛素化活性。我们提出了这个USP7/HAUSP泛素样结构域（HUBL）的晶体结构，由5个泛素样结构域（Ubl）组成，以2-1-2 Ubl单位组织。最后一个双ubl单元，HUBL-45，足以激活USP7，通过与催化区域的“开关”环结合，促进泛素结合并将活性提高100倍。这种激活可以通过代谢酶GMPS变构增强。它结合到前三个Ubl结构域（HUBL-123），并通过稳定hubl -45依赖的活性状态来过度激活USP7。
The ubiquitin-specific protease USP7/HAUSP regulates p53 and MDM2 levels, and cellular localization of FOXO4 and PTEN, and hence is critically important for their role in cellular processes. Here we show how the 64 kDa C-terminal region of USP7 can positively regulate deubiquitinating activity. We present the crystal structure of this USP7/HAUSP ubiquitin-like domain (HUBL) comprised of five ubiquitin-like (Ubl) domains organized in 2-1-2 Ubl units. The last di-Ubl unit, HUBL-45, is sufficient to activate USP7, through binding to a "switching" loop in the catalytic domain, which promotes ubiquitin binding and increases activity 100-fold. This activation can be enhanced allosterically by the metabolic enzyme GMPS. it binds to the first three Ubl domains (HUBL-123) and hyperactivates USP7 by stabilization of the HUBL-45-dependent active state.