Ubiquitin-specific protease 19 (USP19) is a member of the deubiquitinating (DUB) enzymes that catalyze removing the ubiquitin signals from target proteins. Our previous research has demonstrated that USP19 up-regulates the protein level and aggregation of polyQ-expanded huntingtin through the involvement of heat shock protein 90 (HSP90). Here, we present solution structures of the CS1, CS2 and UbL domains of USP19 and structural insights into their domain interactions. We found that the tandem CS domains fold back to interact with the C-terminal USP domain (USPD) intra-molecularly that leads to inhibition of the catalytic core of USP19, especially CS1 interacts with the embedded UbL domain and CS2 does with the CH2 catalytic core. Moreover, CS2 specifically interacts with the NBD domain of HSP90, which can activate the DUB enzyme. A mechanism of auto-inhibition of USP19 and activation by HSP90 is proposed, on which USP19 modulates the protein level of polyQ-expanded huntingtin in cells. This study provides structural and mechanistic insights into the modulation of protein level and aggregation by USP19 with the assistance of HSP90.

中文翻译：

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域相互作用揭示了去泛素化酶USP19的自动抑制及其在Huntingtin聚集调节中的HSP90激活。

泛素特异性蛋白酶19（USP19）是去泛素化（DUB）酶的成员，该酶催化从靶蛋白中去除泛素信号。我们以前的研究表明，USP19通过参与热激蛋白90（HSP90）来上调蛋白质水平和polyQ扩展的亨廷顿蛋白的聚集。在这里，我们介绍了USP19的CS1，CS2和UbL域的解决方案结构，以及对它们的域交互作用的结构见解。我们发现串联CS结构域向后折叠以与C端USP结构域（USPD）相互作用，从而导致抑制USP19的催化核心，尤其是CS1与嵌入的UbL结构域相互作用，而CS2与CH2催化结构相互作用核心。此外，CS2与HSP90的NBD结构域特异性相互作用，可以激活DUB酶。提出了USP19的自动抑制和HSP90激活的机制，在此机制上USP19调节细胞中polyQ扩展的亨廷顿蛋白水平。这项研究为借助HSP90的USP19调节蛋白质水平和聚集提供了结构和机制的见解。