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首页> 外文期刊>Biochemistry >Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1
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Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1

机译：丝氨酸磷酸化对于泛素特异性蛋白酶1的激活及其与WD40重复蛋白UAF1的相互作用至关重要

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摘要

Deubiquitinating enzymes (DUBs) are important for the normal function of a number of cellular processes, including transcriptional regulation, cell cycle control, and DNA damage response. The enzymatic activity of DUB is regulated by different mechanisms. DUBs in several different families are post-translationally modified by phosphorylation. Large-scale phosphoproteomic studies of human DUBs revealed that a majority of ubiquitin-specific proteases (USPs) are phosphorylated. USP1 is a prototypical DUB that requires a specific interaction with a WD40-repeat protein, UAF1, for its catalytic activity. In this study, we show that Ser313 phosphorylation in USP1 is required for its interaction with UAF1 and for the stimulation of USP1's activity. In contrast, two other known USP1 serine phosphorylations (Ser42 and Ser67) are dispensable with respect to the activity of the USP1/UAF1 complex. An S313D phosphomimetic mutation in USP1 can substitute for Ser313 phosphorylation in promoting the formation of the USP1/UAF1 complex. We further demonstrated that CDK1 is responsible for Ser313 phosphorylation, and protein phosphatase treatment of USP1 can lead to inactivation of USP1/UAF1. An inserted domain in USP1 (amino acids 235-408) was found to interact with UAF1, and this interaction is mediated by Ser313 phosphorylation. Our findings revealed an intriguing mechanism of regulating USP1 activity that combines phosphorylation of a key serine residue in USP1 and the specific interaction of USP1 with a WD40-repeat protein UAF1. The pSer313-dependent formation of the USP1/UAF1 complex points to a new approach for inhibiting USP1 activity by disrupting the interaction between the UAF1's WD40-repeat domain and the Ser313-containing phosphopeptide in USP1.
机译：去泛素化酶（DUB）对于许多细胞过程的正常功能很重要，包括转录调控，细胞周期控制和DNA损伤反应。 DUB的酶活性受不同机制的调节。几个不同家族的DUB通过磷酸化进行了翻译后修饰。对人DUB的大规模磷酸化蛋白质组学研究表明，大多数泛素特异性蛋白酶（USP）被磷酸化了。 USP1是一种典型的DUB，其催化活性需要与WD40重复蛋白UAF1发生特异性相互作用。在这项研究中，我们表明USP1中的Ser313磷酸化是其与UAF1相互作用以及刺激USP1活性所必需的。相反，就USP1 / UAF1复合物的活性而言，其他两个已知的USP1丝氨酸磷酸化（Ser42和Ser67）是可有可无的。 USP1中的S313D磷酸模拟突变可替代Ser313磷酸化，从而促进USP1 / UAF1复合物的形成。我们进一步证明CDK1负责Ser313磷酸化，蛋白质磷酸酶处理USP1可以导致USP1 / UAF1失活。发现USP1中的插入域（氨基酸235-408）与UAF1相互作用，并且这种相互作用是通过Ser313磷酸化介导的。我们的发现揭示了一种有趣的调节USP1活性的机制，该机制结合了USP1中关键丝氨酸残基的磷酸化以及USP1与WD40重复蛋白UAF1的特异性相互作用。依赖pSer313的USP1 / UAF1复合物的形成为通过破坏UAF1的WD40重复结构域与USP1中含Ser313的磷酸肽之间的相互作用而抑制USP1活性提供了一种新方法。

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