CUL2-RING泛素连接酶识别羧基端降解子的机制  

Substrate recognition by Cullin-RING ubiquitin ligase and chemical intervention

作　　者：许超 樊新元 高新娇 戚炜 Chao Xu;Xinyuan Fan;Xinjiao Gao;Wei Qi(MOE Key Laboratory for Cellular Dynamics,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230027,China;College of Chemistry and Molecular Engineering,Peking University,Beijing 100871,China;China Gene Editing Center,School of Life Science and Technology,Southwest ShanghaiTech University,Chongqing Shanghai 201210,China)

机构地区：[1]细胞动力学教育部重点实验室,中国科学技术大学生命科学与医学部,合肥230027 [2]北京大学化学与分子工程学院,北京100871 [3]上海科技大学生命科学与技术学院,基因编辑中心,上海201210

出　　处：《中国科学:化学》2025年第4期748-760,共13页SCIENTIA SINICA Chimica

基　　金：国家自然科学基金重大研究计划集成项目(编号:92253301);国家自然科学基金重点项目(编号:22137007)资助。

摘　　要：细胞生命活动的可塑性调控在分子水平表现为生物大分子动态相互作用与稳态调控.泛素-蛋白酶体系统是调控细胞内蛋白质降解的主要途径,其功能异常是导致肿瘤等疾病发生与发展的重要原因.在泛素化级联通路中,泛素连接酶E3负责识别并催化底物聚泛素化.近年来,本研究团队综合利用结构生物学、化学生物学与细胞生物学等方法,解析了Cullin 2-RING泛素连接酶复合物组装机制及其识别底物羧基端降解子的分子机制,阐明了复合物活性受类泛素化修饰激活的机理,并发现了若干可用于设计蛋白降解靶向嵌合体的新靶标.最后,本文展望了未来基于泛素连接酶的底物识别机制开发靶向蛋白质降解剂,以及将该技术与新的化学生物学方法相结合开发新工具的可能性.At the molecular level,the plasticity regulation of cell life activities involves protein-protein dynamic interactions and protein lifetime regulation.The ubiquitin-proteasome system acts as the main route to regulate intracellular protein degradation,and its functional abnormalities are important causes of the occurrence and development of severe human diseases,including tumors.In the ubiquitination cascade pathway,the ubiquitin ligase E3 is responsible for recognizing and catalyzing the polyubiquitination of the substrate.Recently,our team has comprehensively used methods such as structural biology,chemical biology,and cell biology to elucidate the assembly mechanisms of the Cullin 2-RING ubiquitin ligase complexes,as well as the recognition of substrate C-terminal destabilization signals by these complexes.Our recent studies also uncover the mechanism underlying the activation of E3 activity by the neddylation of Cullin-2,and reveal several new targets that can be used in the design of protein degradation-targeting chimeras.Finally,we provide prospects for the future development of targeted protein degraders based on the substrate recognition mechanisms of ubiquitin ligases,as well as the possibility of combining this mechanism with new chemical biology techniques to develop new tools.

关 键 词：泛素化修饰 泛素-蛋白酶体系统 泛素连接酶 羧基端降解子 蛋白降解靶向嵌合体(PROTAC) 

分 类 号：Q55[生物学—生物化学]