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

Xiaojie Yan; Xiaolu Wang; Yao Li; Mengqi Zhou; Yanjun Li; Lili Song; Wenyi Mi; Jinrong Min; Cheng Dong

doi:10.1038/s41589-020-00703-4

Molecular basis for ubiquitin ligase CRL2^FEM1C-mediated recognition of C-degron

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

Authors

Xiaojie Yan^#¹, Xiaolu Wang^#², Yao Li¹, Mengqi Zhou³, Yanjun Li³, Lili Song⁴, Wenyi Mi⁵, Jinrong Min⁶, Cheng Dong⁷

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. [email protected].
⁶ Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto, Ontario, Canada. [email protected].
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. [email protected].

^# 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Arginine / chemistry*
Arginine / metabolism
Binding Sites
Carrier Proteins / chemistry*
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Cycle Proteins / chemistry*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cloning, Molecular
Crystallography, X-Ray
Escherichia coli / genetics
Escherichia coli / metabolism
Gene Expression
Genetic Vectors / chemistry
Genetic Vectors / metabolism
HEK293 Cells
Humans
Models, Molecular
Proteasome Endopeptidase Complex / metabolism*
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Proteolysis
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Substrate Specificity
Ubiquitin-Protein Ligase Complexes / chemistry*
Ubiquitin-Protein Ligase Complexes / genetics
Ubiquitin-Protein Ligase Complexes / metabolism

Substances

Carrier Proteins
Cell Cycle Proteins
FEM1A protein, human
FEM1B protein, human
Recombinant Proteins
Arginine
Fem1c protein, human
Ubiquitin-Protein Ligase Complexes
Proteasome Endopeptidase Complex