Targeted modulation of E3 ligases using engineered ubiquitin variants,The FEBS Journal

当前位置： X-MOL 学术 › FEBS J. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Targeted modulation of E3 ligases using engineered ubiquitin variants
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-08-31 , DOI: 10.1111/febs.15536
Nicole LeBlanc ₁ , Evan Mallette ₁ , Wei Zhang _{1,

2}

Affiliation

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.

中文翻译：

使用工程遍在蛋白变体靶向调节E3连接酶

泛素化在信号转导中起着至关重要的作用，以调节大多数（即使不是全部）细胞过程。在涉及遍在蛋白（Ub）信号级联反应的酶中，人们付出了巨大的努力来阐明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连接酶的功能失常直接涉及许多人类疾病，包括癌症。因此，迫切需要开发有效和特异性的分子来调节E3连接酶的活性，以作为细胞内探针进行靶标验证以及作为临床前研究中的药理剂。不幸的是，针对不同类型的E3连接酶的动态调节机制阻碍了这一进展。这里，我们总结了使用蛋白质工程技术开发E3连接酶的所有主要家族的Ub变体（UbV）抑制剂和与E6相关蛋白C末端E3和同源二聚RING E3同源的UbV激活剂的进展。我们认为，这为研究界抑制或激活E3连接酶提供了一种通用的策略和有价值的工具包，这些合成分子对于探索蛋白质降解的药物发现具有重要意义。

更新日期：2020-08-31

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文