Conditional Protein Function via N-Degron Pathway-Mediated Proteostasis in Stress Physiology

The N-degron pathway, formerly the N-end rule pathway, regulates functions of regulatory proteins. It impacts protein half-life and therefore directs the actual presence of target proteins in the cell. The current concept holds that the N-degron pathway depends on the identity of the amino (N)-terminal amino acid and many other factors, such as the follow-up sequence at theNterminus, conformation, flexibility, and protein localization. It is evolutionarily conserved throughout the kingdoms. One possible entry point for substrates of the N-degron pathway is oxidation of N-terminal Cys residues. Oxidation of N-terminal Cys is decisive for further enzymatic modification of various neo-N termini by arginylation that generates potentially neofunctionalized or instable proteoforms. Here, I focus on the post-translational modifications that are encompassed by protein degradation via the Cys/Arg branch of the N-degron pathway-part of the PROTEOLYSIS 6 (PRT6)/N-degron pathway-as well as the underlying physiological principles of this branch and its biological significance in stress response.