Abstract
The Arg/N-end Rule Pathway and Ubr1, an E3 ligase conserved from yeast to humans, has been demonstrated to be involved in the degradation of misfolded proteins in the cytosol. However, the root physiological purpose of this activity was not completely understood. Through a systematic examination of single residue P2-position mutants of misfolded proteins, followed by global and targeted bioinformatic analyses of the yeast proteome, we have determined that Ubr1 is programmed to preferentially target mistranslocated secretory and mitochondrial proteins in the cytosol. We discovered that degradation by Ubr1 is dependent on the recognition of cellular location signals that are naturally embedded into the 2nd amino acid residue of every protein translated in the cell. This newfound P2-encoded location signaling dependent mechanism for maintaining cytosolic proteomic integrity may shed light on how Ubr1 and the N-end rule pathway are involved in the progression of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, and other maladies linked to the accumulation of misfolded proteins. 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 sub-cellular locations. The N-end rule pathway is thus likely to have been critical to the evolution of endosymbiotic relationships which paved the way for advanced eukaryotic cellular life.
