Degrons are elements within protein substrates that mediate the interaction with specific degradation machineries to control proteolysis. Recently, a few classes of C-terminal degrons (C-degrons) that are recognized by dedicated cullin-RING ligases (CRLs) have been identified. Specifically, CRL2 using the related substrate adapters FEM1A/B/C was found to recognize C degrons ending with arginine (Arg/C-degron). Here, we uncover the molecular mechanism of Arg/C-degron recognition by solving a subset of structures of FEM1 proteins in complex with Arg/C-degron-bearing substrates. Our structural research, complemented by binding assays and global protein stability (GPS) analyses, demonstrates that FEM1A/C and FEM1B selectively target distinct classes of Arg/C-degrons. Overall, our study not only sheds light on the molecular mechanism underlying Arg/C-degron recognition for precise control of substrate turnover, but also provides valuable information for development of chemical probes for selectively regulating proteostasis.

Degrons 是蛋白质底物中的元素，可介导与特定降解机制的相互作用以控制蛋白水解。最近，已经确定了几类被专用 cullin-RING 连接酶 (CRL) 识别的 C 末端降解决定子 (C-degron)。具体而言，发现使用相关底物适配器 FEM1A/B/C 的 CRL2 可识别以精氨酸结尾的 C 去决定子 (Arg/C-去决定子)。在这里，我们通过解决与 Arg/C-degron 底物复合的 FEM1 蛋白的结构子集，揭示了 Arg/C-degron 识别的分子机制。我们的结构研究，辅之以结合测定和全球蛋白质稳定性 (GPS) 分析，表明 FEM1A/C 和 FEM1B 选择性地靶向不同类别的 Arg/C-degrons。总体，