Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
Research Resources Division, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
Commun Biol. 2023 Sep 22;6(1):970. doi: 10.1038/s42003-023-05345-5.
USP47 is widely involved in tumor development, metastasis, and other processes while performing a more regulatory role in inflammatory responses, myocardial infarction, and neuronal development. In this study, we investigate the functional and biochemical properties of USP47, whereby depleting USP47 inhibited cancer cell growth in a p53-dependent manner-a phenomenon that enhances during the simultaneous knockdown of USP7. Full-length USP47 shows higher deubiquitinase activity than the catalytic domain. The crystal structures of the catalytic domain, in its free and ubiquitin-bound states, reveal that the misaligned catalytic triads, ultimately, become aligned upon ubiquitin-binding, similar to USP7, thereby becoming ready for catalysis. Yet, the composition and lengths of BL1, BL2, and BL3 of USP47 differ from those for USP7, and they contribute to the observed selectivity. Our study provides molecular details of USP47 regulation, substrate recognition, and the hotspots for drug discovery by targeting USP47.
USP47 广泛参与肿瘤发生、转移和其他过程，同时在炎症反应、心肌梗死和神经元发育中发挥更具调节作用。在这项研究中，我们研究了 USP47 的功能和生化特性，通过耗尽 USP47 以依赖 p53 的方式抑制癌细胞生长，这种现象在同时敲低 USP7 时会增强。全长 USP47 显示出比催化结构域更高的去泛素化酶活性。催化结构域的晶体结构，无论是在自由状态还是与泛素结合状态，都表明未对齐的催化三联体最终在结合泛素后对齐，类似于 USP7，从而为催化做好准备。然而，USP47 的 BL1、BL2 和 BL3 的组成和长度与 USP7 不同，它们有助于观察到的选择性。我们的研究提供了 USP47 调节、底物识别以及通过靶向 USP47 进行药物发现的热点的分子细节。
