Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON, Canada.
CIFAR Azrieli Global Scholars Program, Canadian Institute for Advanced Research, Toronto, ON, Canada.
FEBS J. 2021 Apr;288(7):2143-2165. doi: 10.1111/febs.15536. Epub 2020 Sep 10.
Ubiquitination plays an essential role in signal transduction to regulate most if not all cellular processes. Among the enzymes that are involved in the ubiquitin (Ub) signaling cascade, tremendous efforts have been focused on elucidating the roles of E3 Ub ligases as they determine the complexity and specificity of ubiquitination. Not surprisingly, the malfunction of E3 ligases is directly implicated in many human diseases, including cancer. Therefore, there is an urgent need to develop potent and specific molecules to modulate E3 ligase activity as intracellular probes for target validation and as pharmacological agents in preclinical research. Unfortunately, the progress has been hampered by the dynamic regulation mechanisms for different types of E3 ligases. Here, we summarize the progress of using protein engineering to develop Ub variant (UbV) inhibitors for all major families of E3 ligases and UbV activators for homologous with E6-associated protein C terminus E3s and homodimeric RING E3s. We believe that this provides a general strategy and a valuable toolkit for the research community to inhibit or activate E3 ligases and these synthetic molecules have important implications in exploring protein degradation for drug discovery.
泛素化在信号转导中起着至关重要的作用，可调节几乎所有的细胞过程。在参与泛素 (Ub) 信号级联的酶中，人们投入了大量精力来阐明 E3 Ub 连接酶的作用，因为它们决定了泛素化的复杂性和特异性。毫不奇怪，E3 连接酶的功能障碍直接与许多人类疾病有关，包括癌症。因此，迫切需要开发有效的、特异性的分子来调节 E3 连接酶的活性，作为细胞内探针来验证靶点，并作为药理学试剂在临床前研究中使用。不幸的是，由于不同类型 E3 连接酶的动态调节机制，这方面的进展受到了阻碍。在这里，我们总结了使用蛋白质工程开发 Ub 变体 (UbV) 抑制剂的进展，这些抑制剂适用于所有主要类型的 E3 连接酶，以及 UbV 激活剂，适用于与 E6 相关蛋白 C 末端 E3 和同源二聚体 RING E3。我们相信，这为研究界提供了一种通用的策略和有价值的工具包，用于抑制或激活 E3 连接酶，这些合成分子在探索蛋白质降解以发现药物方面具有重要意义。
