基于泛素化途径的蛋白质降解策略
首发时间:2019-10-25
摘要:蛋白质是生命活动的主要承担者。从基础研究的角度来看,干扰蛋白质的表达是研究蛋白质功能的有力策略之一。当前,CRISPR技术与RNAi技术被广泛应用于干扰蛋白的表达,但由于这两种途径中蛋白质消耗的非直接性,使得这些方法对靶蛋白的干扰效果强烈受限于蛋白质自身的内在周转。近年来,以PROTACs技术为主导的一类直接在蛋白水平上靶向泛素化降解蛋白的策略引起了生物学家们的广泛关注,这类策略通过招募E3连接酶对目的蛋白进行多聚泛素化,从而介导蛋白经由泛素-蛋白酶体途径实现降解。当前这类方法已经成功降解了多种疾病相关蛋白。实验表明,靶向泛素化降解蛋白的方法不仅具有高效性、高选择性等优势,也解决了小分子抑制剂所面临靶点的"不可成药"的问题,展示出了极大的应用前景。本文将重点介绍和总结靶向泛素化降解蛋白质的相关技术,并剖析这类技术发展的规律与前景。
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Protein degradation strategy based on ubiquitination pathway
Abstract:Proteins are essential constituents of all living organisms. Its expression and degradation are fundamental to cell function and physiological organism. In general, the protein level is precisely regulated by the regulatory network in cells. However, in some cases, abnormal expression and misfolding of protein might occur and often lead to abnormal accumulation of dysfunctional protein in cells, which subsequently lead to the development of various diseases. Therefore, protein interference technology should be explored, which could not only provide an important means to study the function of proteins, but also provide effective prevention and treatment strategies for diseases caused by protein dysfunction. Currently, CRISPR-Cas technology and RNA interfering technology are widely used for interfering proteins\' function. BuResearch on targeted ubiquitination degradation of proteint the interference effect of these methods on target proteins is strongly limited by the inherent turnover of the proteins themselves due to that protein consumption in these two pathways were indirect. In recent years, a class of strategies directly degrading proteins, termed as PROTACs, has attracted wide attention from biologists. The small PROTACs molecules recruited target proteins and E3 ligase, which subsequently catalyzes the ubiquitination of substrates. Then, the protein would be degraded via the ubiquitin-proteasome pathway. PROTACs technology has not only successfully degraded a variety of pathogenic proteins with high efficiency and high selectivity but also solved the "undruggable" issues of small molecule inhibitors, showing great application prospects. This article will focus on the review and summary of technologies that degrade target proteins via ubiquitinating proteins and analyze the development and prospects of such technologies.
Keywords: cytobiology protein degradation ubiquitin-proteasome pathway
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