Specificity profiling of deubiquitylases against endogenously generated ubiquitin-protein conjugates

IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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引用次数: 0

Abstract

Deubiquitylating enzymes (DUBs) remove ubiquitin from proteins thereby regulating their stability or activity. Our understanding of DUB-substrate specificity is limited because DUBs are typically not compared to each other against many physiological substrates. By broadly inhibiting DUBs in Xenopus egg extract, we generated hundreds of ubiquitylated proteins and compared the ability of 30 DUBs to deubiquitylate them using quantitative proteomics. We identified five high-impact DUBs (USP7, USP9X, USP36, USP15, and USP24) that each reduced ubiquitylation of over 10% of the isolated proteins. Candidate substrates of high-impact DUBs showed substantial overlap and were enriched for disordered regions, suggesting this feature may promote substrate recognition. Other DUBs showed lower impact and non-overlapping specificity, targeting distinct non-disordered proteins including complexes such as the ribosome or the proteasome. Altogether our study identifies candidate DUB substrates and defines patterns of functional redundancy and specificity, revealing substrate characteristics that may influence DUB-substrate recognition.

Abstract Image

Abstract Image

去泛素酶对内源性泛素-蛋白质共轭物的特异性分析
去泛素化酶(DUBs)能清除蛋白质中的泛素,从而调节蛋白质的稳定性或活性。我们对DUB-底物特异性的了解很有限,因为DUB通常不会针对许多生理底物进行相互比较。通过广泛抑制爪蟾卵提取物中的 DUBs,我们生成了数百种泛素化蛋白质,并利用定量蛋白质组学比较了 30 种 DUBs 对它们进行去泛素化的能力。我们发现了五种高影响 DUBs(USP7、USP9X、USP36、USP15 和 USP24),每种 DUBs 都能减少 10% 以上分离蛋白的泛素化。高影响 DUB 的候选底物显示出大量重叠,并且富含无序区域,这表明这一特征可能会促进底物识别。其他 DUBs 显示出较低的影响和非重叠特异性,它们以不同的非无序蛋白为靶标,包括核糖体或蛋白酶体等复合物。总之,我们的研究确定了候选的 DUB 底物,定义了功能冗余和特异性模式,揭示了可能影响 DUB 底物识别的底物特征。
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来源期刊
Cell Chemical Biology
Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍: Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.
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