How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini

• Published in: Molecular cell Vol. 82; no. 8; pp. 1424 - 1438
• Main Authors: Sherpa, Dawafuti, Chrustowicz, Jakub, Schulman, Brenda A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.04.2022; Cell Press
• Subjects: Amino Acid Motifs; C-degron; cullin-RING ligase; E3 ligase; GID complex; N-degron; N-end rule; protein degradation; protein quality control; protein value; Proteins - metabolism; Proteolysis; Review; ribosomes; ubiquitin; Ubiquitin - metabolism; ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; UBR; N-degron; E3 ligase; cullin-RING ligase; UBR; protein quality control; N-end rule; GID complex; ubiquitin; C-degron
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2022.02.004

Specificity of eukaryotic protein degradation is determined by E3 ubiquitin ligases and their selective binding to protein motifs, termed “degrons,” in substrates for ubiquitin-mediated proteolysis. From the discovery of the first substrate degron and the corresponding E3 to a flurry of recent studies enabled by modern systems and structural methods, it is clear that many regulatory pathways depend on E3s recognizing protein termini. Here, we review the structural basis for recognition of protein termini by E3s and how this recognition underlies biological regulation. Diverse E3s evolved to harness a substrate's N and/or C terminus (and often adjacent residues as well) in a sequence-specific manner. Regulation is achieved through selective activation of E3s and also through generation of degrons at ribosomes or by posttranslational means. Collectively, many E3 interactions with protein N and C termini enable intricate control of protein quality and responses to cellular signals. In this review, Sherpa et al. (2022) discuss how protein termini often serve as degradation signals recognized by recurrent folds within E3 ligases, how terminal degron pathways are regulated through modulation of E3 ligases and conditional degron generation, and how these pathways may be useful platforms for the development of therapeutics.