Structural and biochemical elements of efficiently degradable proteasome substrates
Structural and biochemical elements of efficiently degradable proteasome substrates
复制标题
高效可降解蛋白酶体底物的结构和生化元件
DOI：
10.1093/jb/mvab157
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Tomita Takuya
中科院分区：
文献类型：
--
作者：
冨田 拓哉;Tomita Takuya
细胞中最受调控的蛋白分解是由泛素-蛋白酶体系统(UPS)进行的，在UPS中，通过多个步骤选择要消除的蛋白质以获得高特异性。大的蛋白酶复合蛋白酶体与附着在底物上的泛素分子结合，并进一步与靶标中的无序区域相互作用，启动展开以进行降解。最近的研究扩大了我们对泛素化的复杂性以及蛋白酶体与底物结合的细节的看法，同时也揭示了对蛋白酶体降解敏感的底物的特征。在这里，我综述了蛋白酶体底物的一些不稳定因素，特别是泛素化、起始区和对去折叠的稳定性，并讨论了它们之间的相互作用，以确定底物的稳定性。空间视角对于理解蛋白酶体降解的作用机制是重要的，这对于靶向UPS的药物开发包括靶向蛋白降解可能是至关重要的。
Most regulated proteolysis in cells is conducted by the ubiquitin-proteasome system (UPS), in which proteins to be eliminated are selected through multiple steps to achieve high specificity. The large protease complex proteasome binds to ubiquitin molecules that are attached to the substrate and further interacts with a disordered region in the target to initiate unfolding for degradation. Recent studies have expanded our view of the complexity of ubiquitination as well as the details of substrate engagement by the proteasome and at the same time have suggested the characteristics of substrates that are susceptible to proteasomal degradation. Here, I review some destabilizing elements of proteasome substrates with particular attention to ubiquitination, initiation region and stability against unfolding and discuss their interplay to determine the substrate stability. A spatial perspective is important to understand the mechanism of action of proteasomal degradation, which may be critical for drug development targeting the UPS including targeted protein degradation.