Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-degron

Nat Chem Biol. 2021 Mar;17(3):263-271. doi: 10.1038/s41589-020-00703-4.

Xiaojie Yan ^# ¹, Xiaolu Wang ^# ², Yao Li ¹, Mengqi Zhou ³, Yanjun Li ³, Lili Song ⁴, Wenyi Mi ⁵, Jinrong Min ⁶, Cheng Dong ⁷

Affiliations

1 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.
2 Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
3 Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
4 Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Diseases and Microenvironment of Ministry of Education of China, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
5 Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Diseases and Microenvironment of Ministry of Education of China, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. wenyi.mi@tmu.edu.cn.
6 Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto, Ontario, Canada. jr.min@utoronto.ca.
7 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. dongcheng@tmu.edu.cn.
# Contributed equally.

PMID: 33398170 DOI: 10.1038/s41589-020-00703-4

Abstract

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.

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