The yeast Pma1 proton pump: a model for understanding the biogenesis of plasma membrane proteins.

The Pma1 H -ATPase of Saccharomyces cerevisiae, which functions physiologically to pump protons out of the cell, is one of the most abundant proteins in the yeast plasma membrane (1). It is a 100-kDa polypeptide, anchored in the membrane by 10 hydrophobic -helices (Fig. 1) (2) and belonging to a widespread family of cation transporters known as the P2-type ATPases (6). Members of the P2 family in animal cells include the plasma membrane Na ,K and Ca -ATPases, gastric mucosal H , K -ATPase, and sarcoplasmic reticulum Ca -ATPase. In recent years, the yeast H -ATPase has emerged as a valuable prototype for studies of plasma membrane biogenesis. Several complementary approaches have been taken, all drawing on the power of yeast genetics. (i) Strains with temperature-sensitive blocks at successive steps in the secretory pathway have made it possible to map the route by which the H -ATPase travels to the plasma membrane (7–9). (ii) Point mutations in the PMA1 gene have given insights into the structural requirements for proper folding and trafficking of the H -ATPase (10–13). (iii) Suppressors and enhancers of biogenesis-defective pma1 mutants have revealed new components of the secretory process (14–18). (iv) Finally, by screening for mutations that exacerbate a temperature-sensitive defect in one of the standard COPII coat subunits, a specialized coat protein has been identified that helps to mediate the exit of newly synthesized H -ATPase from the ER (19, 20). In the following sections, recent results from all four approaches are woven together into a stepwise description of H -ATPase biogenesis. A comprehensive review of earlier work can be found in a chapter by de Kerchove d’Exaerde et al. (21).