1. Recognition of the Diglycine C-End Degron by CRL2 KLHDC2 Ubiquitin Ligase.
- Author
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Rusnac DV, Lin HC, Canzani D, Tien KX, Hinds TR, Tsue AF, Bush MF, Yen HS, and Zheng N
- Subjects
- Amino Acid Sequence, Animals, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Baculoviridae genetics, Baculoviridae metabolism, Binding Sites, Cloning, Molecular, Crystallography, X-Ray, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression, Genetic Vectors chemistry, Genetic Vectors metabolism, Glycylglycine metabolism, HEK293 Cells, Humans, Kinetics, Molecular Docking Simulation, Proteasome Endopeptidase Complex metabolism, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Selenoproteins genetics, Selenoproteins metabolism, Spodoptera, Substrate Specificity, Ubiquitin-Specific Proteases genetics, Ubiquitin-Specific Proteases metabolism, Antigens, Neoplasm chemistry, Glycylglycine chemistry, Selenoproteins chemistry, Ubiquitin-Specific Proteases chemistry
- Abstract
Aberrant proteins can be deleterious to cells and are cleared by the ubiquitin-proteasome system. A group of C-end degrons that are recognized by specific cullin-RING ubiquitin E3 ligases (CRLs) has recently been identified in some of these abnormal polypeptides. Here, we report three crystal structures of a CRL2 substrate receptor, KLHDC2, in complex with the diglycine-ending C-end degrons of two early-terminated selenoproteins and the N-terminal proteolytic fragment of USP1. The E3 recognizes the degron peptides in a similarly coiled conformation and cradles their C-terminal diglycine with a deep surface pocket. By hydrogen bonding with multiple backbone carbonyls of the peptides, KLHDC2 further locks in the otherwise degenerate degrons with a compact interface and unexpected high affinities. Our results reveal the structural mechanism by which KLHDC2 recognizes the simplest C-end degron and suggest a functional necessity of the E3 to tightly maintain the low abundance of its select substrates., (Published by Elsevier Inc.)
- Published
- 2018
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