The N-end rule pathway and Ubr1 enforce protein compartmentalization via P2-encoded cellular location signals.

The Arg/N-end rule pathway and Ubr1, a ubiquitin E3 ligase conserved from yeast to humans, is involved in the degradation of misfolded proteins in the cytosol. However, the root physiological purpose of this activity is not completely understood. Through a systematic examination of single-residue P2-position mutants of misfolded proteins, and global and targeted bioinformatic analyses of the Saccharomyces cerevisiae proteome, it was determined that Ubr1 preferentially targets mistranslocated secretory and mitochondrial proteins in the cytosol. Degradation by Ubr1 is dependent on the recognition of cellular location signals that are naturally embedded into the second amino acid residue of most proteins. This P2-encoded location signaling mechanism may shed light on how Ubr1 and the N-end rule pathway are involved in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A corollary to this discovery is that the N-end rule pathway enforces the compartmentalization of secretory and mitochondrial proteins by degrading those that fail to reach their intended subcellular locations. The N-end rule pathway is therefore likely to have been critical to the evolution of endosymbiotic relationships that paved the way for advanced eukaryotic cellular life. This article has an associated First Person interview with the first author of the paper.