Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3 ligase

Xinyan Chen, Shanhui Liao, Yaara Makaros, Qiong Guo, Zhongliang Zhu, Rina Krizelman, Karin Dahan, Xiaoming Tu, Xuebiao Yao, Itay Koren, Chao Xu

Research output: Contribution to journalArticlepeer-review


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. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)254-262
Number of pages9
JournalNature Chemical Biology
Issue number3
Early online date4 Jan 2021
StatePublished - Mar 2021

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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