Journal of Proteomics ( IF 2.8 ) Pub Date : 2020-10-02 , DOI: 10.1016/j.jprot.2020.103996 Zhanhong Hu 1 , Hongcheng Li 2 , Xiaohui Wang 2 , Kifayat Ullah 2 , Guoqiang Xu 2
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Protein ubiquitylation regulates almost all aspects of the biological processes including gene expression, DNA repair, cell proliferation and apoptosis in eukaryotic cells. Dysregulation of protein ubiquitylation caused by abnormal expression of enzymes in the ubiquitin system results in the onset of many diseases including cancer, neurodegenerative diseases, and metabolic syndromes. Therefore, targeting the ubiquitin system becomes a promising research area in drug discovery. Identification of protein ubiquitylation sites is critical for revealing the key ubiquitylation events associated with diseases and specific signaling pathways and for elucidating the biological functions of the specific ubiquitylation events. Many approaches that enrich for the ubiquitylated proteins and ubiquitylated peptides at the protein and peptide levels have been developed to facilitate their identification by MS. In this paper, we will review the proteomic approaches available for the identification of ubiquitylation events at the proteome scale and discuss their advantages and limitations. We will also brief the application of the profiling of ubiquitylation events in drug target discovery and in target validation for proteolysis-targeting chimera (PROTAC). Possible future research directions in this field will also be discussed.
Significance
Ubiquitylation plays critical roles in regulating many biological processes in eukaryotic cells. Identification of ubiquitylation sites can provide the essential information for the functional study of the specific modified substrates. Since ubiquitylated proteins have much lower abundance than non-ubiquitylated proteins, enrichment of ubiquitylated proteins or peptides is critical for their identification by MS. This review focuses on different enrichment approaches that facilitate their isolation and identification by MS and discusses the advantages and drawbacks of these approaches. The application of the profiling of ubiquitylation events in drug target discovery and future research directions will be beneficial to the research community.
中文翻译：
蛋白质组学方法用于泛素化事件的概况分析及其在药物发现中的应用
蛋白质泛素化调节了生物过程的几乎所有方面，包括基因表达，DNA修复，真核细胞中的细胞增殖和凋亡。由泛素系统中酶的异常表达引起的蛋白质泛素化失调导致许多疾病的发作，包括癌症，神经退行性疾病和代谢综合征。因此，以泛素系统为靶标成为药物开发中一个有前途的研究领域。蛋白质泛素化位点的鉴定对于揭示与疾病和特定信号通路相关的关键泛素化事件以及阐明特定泛素化事件的生物学功能至关重要。已经开发出许多在蛋白质和肽水平上富集泛素化蛋白和泛素化肽的方法，以利于通过MS对其进行鉴定。在本文中，我们将回顾可用于蛋白质组学规模泛素化事件鉴定的蛋白质组学方法，并讨论其优势和局限性。我们还将简要介绍泛素化事件分析在药物靶标发现和蛋白水解靶向嵌合体（PROTAC）的靶标验证中的应用。还将讨论该领域可能的未来研究方向。我们还将简要介绍泛素化事件分析在药物靶标发现和蛋白水解靶向嵌合体（PROTAC）的靶标验证中的应用。还将讨论该领域可能的未来研究方向。我们还将简要介绍泛素化事件分析在药物靶标发现和蛋白水解靶向嵌合体（PROTAC）的靶标验证中的应用。还将讨论该领域可能的未来研究方向。
意义
泛素化在调节真核细胞的许多生物学过程中起着关键作用。泛素化位点的鉴定可以为特定修饰底物的功能研究提供必要的信息。由于泛素化蛋白的丰度比非泛素化蛋白低得多，因此富集泛素化蛋白或肽对于通过质谱鉴定它们至关重要。这篇综述着重于有助于MS分离和鉴定的各种富集方法，并讨论了这些方法的优缺点。泛素化事件的概况分析在药物靶标发现和未来研究方向中的应用将对研究界有益。
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