New Mechanisms and Functions of the Pro/N Degron and Arg/N-Degron Pathways

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Project Summary/Abstract Regulated proteolysis by the ubiquitin-proteasome system (ubiquitin system) plays essential roles in a multitude of biological processes and has major ramifications for human health and disease, including illnesses that range from cancer and neurodegeneration to cardiovascular syndromes and defects of immunity. Our studies of the ubiquitin-proteasome system and ubiquitin-dependent N-degron pathways (previously called “N-end rule pathways”) over more than three decades were made possible, to a large extent, by the present grant (DK039520), currently in its 34th year of support. N-degron pathways recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, polyubiquitylate these proteins and thereby cause their degradation by the proteasome or autophagy. Recognition components of N-degron pathways, called N-recognins, are E3 ubiquitin ligases that can target N-degrons. One eukaryotic N-degron pathway, called the Arg/N-degron pathway, targets, in particular, specific unmodified Nt-residues of protein substrates. Another Nt-proteolytic system, called the Pro/N-degron pathway, recognizes, in particular, the Nt-proline (Pro) residue of protein substrates. This DK039520 renewal application stems from our unpublished studies over the last ~2 years, and focuses on the yeast (S. cerevisiae) Pro/N-degron and Arg/N-degron pathways, including the functions of specific aminopeptidases and the recently discovered ability of Ubr1, the E3 of the Arg/N-degron pathway, to target not only N-degrons but also C-degrons. These and related studies, described in Specific Aims of the DK039520 renewal application, will advance the understanding of protein degradation and the universally present (as well as medically significant) N-degron pathways.