ABSTRACT
Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are widely associated with the buildup of misfolded proteins. Cells have evolved intricate systems of protein quality control (PQC) that serve to monitor the cell for aberrant proteins and target them for degradation, ameloriating the effects of the majority of folding failures. In recent years, Ubr1, an E3 ligase conserved from yeast to humans, has been demonstrated to be involved in the degradation of several misfolded substrates within the cytosol through the Arg/N-end rule pathway, but the significance of this activity was not completely understood. Through a systematic examination of P2-residue variants of model misfolded substrates, followed by global and targeted analyses of yeast proteins, we have determined that Ubr1 is specifically programmed to preferentially target mistranslocated secretory and mitochondrial proteins in the cytosol. Significantly, this newfound specialized functionality may shed light on how Ubr1 and the N-end rule pathway are at play in the onset of neurodegenerative diseases in humans.