Ravalin Matthew, Basu Koli, Gestwicki Jason E, Craik Charles S
Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94143, United States.
Institute for Neurodegenerative Diseases, University of California at San Francisco, San Francisco, California 94143, United States.
ACS Chem Biol. 2021 Nov 19;16(11):2047-2056. doi: 10.1021/acschembio.9b00621. Epub 2019 Nov 20.
Post-translational modifications (PTMs) direct the assembly of protein complexes. In this context, proteolysis is a unique PTM because it is irreversible; the hydrolysis of the peptide backbone generates separate fragments bearing a new N and C terminus. Proteolysis can "re-wire" protein-protein interactions (PPIs) the recruitment of end-binding proteins to new termini. In this review, we focus on the role of proteolysis in specifically creating complexes by recruiting E3 ubiquitin ligases to new N and C termini. These complexes potentiate proteolytic signaling by "erasing" proteolytic modifications. This activity tunes the duration and magnitude of protease signaling events. Recent work has shown that the stepwise process of proteolysis, end-binding by E3 ubiquitin ligases, and fragment turnover is associated with both the nascent N terminus (i.e., N-degron pathways) and the nascent C terminus (i.e., the C-degron pathways). Here, we discuss how these pathways might harmonize protease signaling with protein homeostasis (i.e., proteostasis).
翻译后修饰（PTMs）指导蛋白质复合物的组装。在这种情况下，蛋白水解是一种独特的翻译后修饰，因为它是不可逆的；肽主链的水解产生带有新的N端和C端的单独片段。蛋白水解可以“重新连接”蛋白质-蛋白质相互作用（PPIs），即将末端结合蛋白招募到新的末端。在本综述中，我们重点关注蛋白水解在通过将E3泛素连接酶招募到新的N端和C端来特异性形成复合物方面的作用。这些复合物通过“消除”蛋白水解修饰来增强蛋白水解信号传导。这种活性调节蛋白酶信号传导事件的持续时间和强度。最近的研究表明，蛋白水解、E3泛素连接酶的末端结合以及片段周转的逐步过程与新生的N端（即N-降解子途径）和新生的C端（即C-降解子途径）都有关联。在这里，我们讨论这些途径如何使蛋白酶信号传导与蛋白质稳态（即蛋白质平衡）相协调。
