부산대학교 도서관

Proteolysis-assisted protein quality control system guards the proteome from potentially detrimental aberrant proteins. How miscellaneous forms of aberrant proteins are specifically eliminated and what features direct their degradation are fundamental questions. Here, we unveil a novel function of CRL2 ubiquitin ligases in proteolysis-assisted protein quality control. We identified 54 CRL2 substrates of which were highly enriched in defectives. CRL2 selectively recognizes the unusual C-termini of defective proteins. CRL2 utilizes interchangeable substrate receptors to target various protein C-termini. The C-termini of aberrant proteins are sufficient as C-terminal-specific protein degradation signals (C-end degrons). C-end degrons are composed of a few pivotal residues generally within a length of 10 amino acids. The penetrance of identified C-end degrons are revealed by the degradation propensities of random peptides carrying C-end degron features. Physiological substrates of CRL2 include prematurely terminated selenoproteins and N-terminal fragment of auto-cleaved USP1. CRL2 also targets full-length proteins with innate C-end degrons, suggesting a function of CRL2 beyond protein quality control. Bioinformatics analysis showed that C-end degrons are disfavored at the C-termini of eukaryotic proteome, suggesting the modulation of proteome composition by C-end degron-directed protein degradation. Our findings reveal a function of CRL2 in protein quality surveillance and define the DesCEND (Destruction via C-ENd Degrons) protein degradation mechanism. DesCEND echoes the N-end rule, of which emphasizes the effect of N-terminal amino acid residues in protein degradation, and poses significance of protein termini in regulating protein half-lives.