Chemical methods for protein site-specific ubiquitination.
Chemical methods for protein site-specific ubiquitination.
复制标题
DOI：
10.1039/d0cb00215a
复制
发表时间：
2021-04-01
影响因子：
4.1
通讯作者：
Zhuang Z
中科院分区：
文献类型：
--
作者：
Gui W;Davidson GA;Zhuang Z
泛素化是真核生物中一种重要的蛋白质翻译后修饰，调节着许多细胞过程。泛素化由三酶级联催化，导致泛素（Ub）的C-末端羧酸酯通过异肽键与受体蛋白中赖氨酸残基的ε-氨基缀合。利用Ub连接酶的体外酶促泛素化已成功地用于产生Ub二聚体和聚合物。然而，酶促方法存在局限性，特别是由于对于任何给定的靶蛋白需要特异性Ub连接酶以及Ub连接酶的低催化效率。为了深入了解Ub信号传导的分子机制，需要新的方法来产生在特定位点具有定义的多聚泛素链连接和长度的单和多聚泛素化蛋白。化学方法为上述挑战提供了有吸引力的解决方案。在这篇综述中，我们总结了最近开发的化学方法，利用合成和半合成的方法产生泛素化蛋白。这些新的工具和方法，作为Ub工具箱的重要组成部分，对于我们理解和利用Ub系统进行新的治疗至关重要。蛋白质位点特异性泛素化的化学方法对于理解Ub信号传导是重要的。
Ubiquitination is an important protein post-translational modification regulating many cellular processes in eukaryotes. Ubiquitination is catalyzed by a three-enzyme cascade resulting in the conjugation of the C-terminal carboxylate of ubiquitin (Ub) to the ε-amino group of a lysine residue in the acceptor protein via an isopeptide bond. In vitro enzymatic ubiquitination utilizing Ub ligases has been successfully employed to generate Ub dimers and polymers. However, limitations of the enzymatic approach exist, particularly due to the requirement of specific Ub ligase for any given target protein and the low catalytic efficiency of the Ub ligase. To achieve an in-depth understanding of the molecular mechanism of Ub signaling, new methods are needed to generate mono- and poly-ubiquitinated proteins at a specific site with defined polyubiquitin chain linkage and length. Chemical methods offer an attractive solution to the above-described challenges. In this review, we summarize the recently developed chemical methods for generating ubiquitinated proteins using synthetic and semisynthetic approaches. These new tools and approaches, as an important part of the Ub toolbox, are crucial to our understanding and exploitation of the Ub system for novel therapeutics. Chemical methods for protein site-specific ubiquitination are important for the understanding of Ub signaling.