N-TERMINAL DETERMINANTS OF CYTOSOLIC PROTEIN QUALITY CONTROL

Abstract

In yeast, the San1p and Ubr1p E3 ligases target cytosolic misfolded proteins for degradation. While San1p and Ubr1p are known to exhibit partially overlapping specificity for misfolded substrates, differences in their means of target recognition were unclear. Ubr1p is a mediator of the N-end rule pathway, which relates the half-life of a protein to the identity of its N-terminal residue. In this study, we discovered a link between Ubr1p¿s affinity for specific novel destabilizing N-terminal sequences, or N-degrons, and its function in protein quality control. This led us to propose a new model for Ubr1 quality control in which a subset of proteins that undergo translocation failure, and are thus aberrantly localized to the cytosol, become subject to Ubr1-mediated quality control by virtue of harboring a bi-partite signal comprising a destabilizing N-terminal sequence and conformational aberrancy. Our analysis of several representative mis-translocated mitochondrial and secretory pathway proteins confirms our model.