How are proteins sorted in the secretory pathway?

Background: The yeast plasma membrane ATPase, Pma1, is an abundant polytopic membrane protein whose function is to regulate cytosolic pH and generate the membrane potential by pumping protons out of the cell.  This activity is essential for cell growth.  We have been studying several Pma1 mutants conditionally defective in localization to the cell surface.  These mutants are all conformationally impaired but handled by the cell’s quality control systems in different ways:  Pma1-D378N is a substrate for ER-associated degradation. Pma1-7 escapes ER quality control but is routed to the endosomal/vacuolar pathway for degradation. A third mutant, Pma1-10, is properly targeted to the plasma membrane but its ubiquitination appears to signal endocytosis and prevents acquisition of cell surface stability.  To understand better the quality control mechanisms that recognize misfolded proteins, we have taken a genetic approach to identify suppressors of each of the pma1 mutants. In this way, we are identifying the molecular components involved in diverse quality control mechanisms.