Division of Biochemistry and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Mol Cell. 2011 Oct 7;44(1):147-59. doi: 10.1016/j.molcel.2011.06.034.
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.
泛素特异性蛋白酶 USP7/HAUSP 调节 p53 和 MDM2 的水平和 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 末端区域如何正向调节去泛素化活性。我们呈现了由五个泛素样（Ubl）结构域组成的 USP7/HAUSP 泛素样结构域（HUBL）的晶体结构，这些结构域以 2-1-2 Ubl 单元的形式组织。最后一个双 Ubl 单元 HUBL-45 通过与催化结构域中的“切换”环结合足以激活 USP7，促进泛素结合并使活性增加 100 倍。这种激活可以通过代谢酶 GMPS 进行变构增强。它与前三个 Ubl 结构域（HUBL-123）结合，并通过稳定 HUBL-45 依赖性活性状态来超激活 USP7。
