Department of Biochemistry and Molecular Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Nat Chem Biol. 2021 Mar;17(3):263-271. doi: 10.1038/s41589-020-00703-4. Epub 2021 Jan 4.
Proteome integrity depends on the ubiquitin-proteasome system to degrade unwanted or abnormal proteins. In addition to the N-degrons, C-terminal residues of proteins can also serve as degradation signals (C-degrons) that are recognized by specific cullin-RING ubiquitin ligases (CRLs) for proteasomal degradation. FEM1C is a CRL2 substrate receptor that targets the C-terminal arginine degron (Arg/C-degron), but the molecular mechanism of substrate recognition remains largely elusive. Here, we present crystal structures of FEM1C in complex with Arg/C-degron and show that FEM1C utilizes a semi-open binding pocket to capture the C-terminal arginine and that the extreme C-terminal arginine is the major structural determinant in recognition by FEM1C. Together with biochemical and mutagenesis studies, we provide a framework for understanding molecular recognition of the Arg/C-degron by the FEM family of proteins.
蛋白质组的完整性依赖于泛素-蛋白酶体系统来降解不需要或异常的蛋白质。除了 N 端降解信号，蛋白质的 C 末端残基也可以作为降解信号（C 端降解信号），被特定的 Cullin-RING 泛素连接酶（CRL）识别，进行蛋白酶体降解。FEM1C 是 CRL2 底物受体，靶向 C 末端精氨酸降解信号（Arg/C 降解信号），但底物识别的分子机制在很大程度上仍难以捉摸。在这里，我们展示了 FEM1C 与 Arg/C 降解信号复合物的晶体结构，并表明 FEM1C 利用半开放的结合口袋来捕获 C 末端精氨酸，而极端 C 末端精氨酸是 FEM1C 识别的主要结构决定因素。结合生化和突变研究，我们为理解 FEM 蛋白家族对 Arg/C 降解信号的分子识别提供了一个框架。
