The Yeast Pma1 Proton Pump: a Model for Understanding the Biogenesis of Plasma Membrane Proteins

endoplasmic reticulum The Pma1 H+-ATPase ofSaccharomyces cerevisiae, which functions physiologically to pump protons out of the cell, is one of the most abundant proteins in the yeast plasma membrane (1Morsomme P. Slayman C.W. Goffeau A. Mutagenic study of the structure, function, and biogenesis of the yeast plasma membrane H+-ATPase..Biochim. Biophys. Acta. 2000; 1469 (review): 133-157Crossref PubMed Scopus (103) Google Scholar). It is a 100-kDa polypeptide, anchored in the membrane by 10 hydrophobic α-helices (Fig.1) (2Auer M. Scarborough G.A. Kuhlbrandt W. Three-dimensional map of the plasma membrane H+-ATPase in the open conformation..Nature. 1998; 392: 840-843Crossref PubMed Scopus (185) Google Scholar) and belonging to a widespread family of cation transporters known as the P2-type ATPases (6Lutsenko S. Kaplan J.H. Organization of P-type ATPases: significance of structural diversity..Biochemistry. 1995; 34: 15607-15613Crossref PubMed Scopus (418) Google Scholar). Members of the P2 family in animal cells include the plasma membrane Na+,K+- and Ca2+-ATPases, gastric mucosal H+, K+-ATPase, and sarcoplasmic reticulum Ca2+-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 (7Brada D. Schekman R. Coincident localization of secretory and plasma membrane proteins in organelles of the yeast secretory pathway..J. Bacteriol. 1988; 1780: 2775-2783Crossref Google Scholar, 8Holcomb C.L. Hansen W.J. Etcheverry T. Schekman R. Secretory vesicles externalize the major plasma membrane ATPase in yeast..J. Cell Biol. 1988; 106: 641-648Crossref PubMed Scopus (47) Google Scholar, 9Chang A. Slayman C.W. Maturation of the yeast plasma membrane [H+]ATPase involves phosphorylation during intracellular transport..J. Cell Biol. 1991; 115: 289-295Crossref PubMed Scopus (151) Google Scholar). (ii) Point mutations in the PMA1 gene have given insights into the structural requirements for proper folding and trafficking of the H+-ATPase (10Harris S.L. Na S. Zhu X. Seto-Young D. Perlin D.S. Teem J.H. Haber J.E. Dominant lethal mutations in the plasma membrane H+-ATPase gene of Saccharomyces cerevisiae..Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10531-10535Crossref PubMed Scopus (62) Google Scholar, 11Portillo F. Characterization of dominant lethal mutations in the yeast plasma membrane H+-ATPase gene..FEBS Lett. 1997; 402: 136-140Crossref PubMed Scopus (28) Google Scholar, 12Nakamoto R.K. Verjovski-Almeida S. Allen K.E. Ambesi A. Rao R. Slayman C.W. Substitutions of aspartate 378 in the phosphorylation domain of the yeast PMA1 H+-ATPase disrupt protein folding and biogenesis..J. Biol. Chem. 1998; 273: 7338-7344Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 13DeWitt N.D. Tourinho dos Santos C.F. Allen K.E. Slayman C.W. Phosphorylation region of the yeast plasma membrane H+-ATPase. Role in protein folding and biogenesis..J. Biol. Chem. 1998; 273: 21744-21751Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). (iii) Suppressors and enhancers of biogenesis-defective pma1 mutants have revealed new components of the secretory process (14Chang A. Fink G.R. Targeting of the yeast plasma membrane [H+]ATPase: a novel gene AST1 prevents mislocalization of the ATPase to the vacuole..J. Cell Biol. 1995; 128: 39-49Crossref PubMed Scopus (94) Google Scholar, 15Na S. Hincapie M. McCusker J.H. Haber J.E. MOP2 (SLA2) affects the abundance of the plasma membrane H+-ATPase of Saccharomyces cerevisiae..J. Biol. Chem. 1995; 270: 6815-6823Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 16Luo W. Chang A. Novel genes involved in endosomal traffic in yeast revealed by suppression of a targeting-defective plasma membrane ATPase mutant..J. Cell Biol. 1997; 138: 731-746Crossref PubMed Scopus (91) Google Scholar, 17Wang Q. Chang A. Eps1, a novel PDI-related protein involved in ER quality control in yeast..EMBO J. 1999; 18: 5972-5982Crossref PubMed Scopus (88) Google Scholar, 18Luo W. Chang A. An endosome-to-plasma membrane pathway involved in trafficking of a mutant plasma membrane ATPase in yeast..Mol. Biol. Cell. 2000; 11: 579-592Crossref PubMed Scopus (64) Google Scholar). (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 ER1 (19Roberg K.J. Crotwell M. Espenshade P. Gimeno R. Kaiser C.A. LST1 is a SEC24 homologue used for selective export of the plasma membrane ATPase from the endoplasmic reticulum..J. Cell Biol. 1999; 145: 659-672Crossref PubMed Scopus (130) Google Scholar, 20Shimoni Y. Kurihara T. Ravazzola M. Amherdt M. Orci L. Schekman R. Lst1p and Sec24p cooperate in sorting of the plasma membrane ATPase into COPII vesicles in Saccharomyces cerevisiae..J. Cell Biol. 2000; 151: 973-984Crossref PubMed Scopus (116) Google Scholar). 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. (21Kerchove d'Exaerde A. Supply P. Goffeau A. Subcellular traffic of the plasma membrane H+-ATPase in Saccharomyces cerevisiae..Yeast. 1996; 12: 907-916Crossref PubMed Scopus (30) Google Scholar). As expected, Pma1 H+-ATPase is synthesized and integrated into the membrane in the rough endoplasmic reticulum. Pulse-chase experiments suggest that it achieves a fully folded structure very rapidly, because it can be protected against trypsinolysis by physiological concentrations of ligands even at the earliest time points (22Chang A. Rose M.D. Slayman C.W. Folding and intracellular transport of the yeast plasma membrane H+-ATPase: effects of mutations in KAR2SEC65..Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 5808-5812Crossref PubMed Scopus (13) Google Scholar). The ATPase then travels to the cell surface via the secretory pathway (Fig. 2), as shown by the fact that its biogenesis can be blocked by temperature-sensitive mutations in genes governing successive steps of the pathway: SEC18 (ER to Golgi), SEC7 (Golgi to secretory vesicles), and SEC6 (secretory vesicles to plasma membrane) (8Holcomb C.L. Hansen W.J. Etcheverry T. Schekman R. Secretory vesicles externalize the major plasma membrane ATPase in yeast..J. Cell Biol. 1988; 106: 641-648Crossref PubMed Scopus (47) Google Scholar, 9Chang A. Slayman C.W. Maturation of the yeast plasma membrane [H+]ATPase involves phosphorylation during intracellular transport..J. Cell Biol. 1991; 115: 289-295Crossref PubMed Scopus (151) Google Scholar). Interestingly, the 100-kDa H+-ATPase undergoes post-translational phosphorylation on multiple Ser and Thr residues during its transit from the ER to the cell surface (9Chang A. Slayman C.W. Maturation of the yeast plasma membrane [H+]ATPase involves phosphorylation during intracellular transport..J. Cell Biol. 1991; 115: 289-295Crossref PubMed Scopus (151) Google Scholar). The functional reason for these stepwise phosphorylations is unknown, although there is good evidence that the last one, occurring at or near the plasma membrane, plays a role in the activation of the ATPase by glucose (9Chang A. Slayman C.W. Maturation of the yeast plasma membrane [H+]ATPase involves phosphorylation during intracellular transport..J. Cell Biol. 1991; 115: 289-295Crossref PubMed Scopus (151) Google Scholar). The oligomeric state of the mature H+-ATPase is not yet certain. Monomers of the closely related Neurospora crassaenzyme are fully active after reconstitution into proteoliposomes (23Scarborough G.A. Addison R. On the subunit composition of the Neurospora plasma membrane H+-ATPase..J. Biol. Chem. 1984; 259: 9109-9114Abstract Full Text PDF PubMed Google Scholar), but radiation inactivation experiments give a target size of 230 kDa, consistent with a functional dimer (24Bowman B.J. Berenski C.J. Jung C.Y. Size of the plasma membrane H+-ATPase from Neurospora crassa determined by radiation inactivation..J. Biol. Chem. 1985; 260: 8726-8730Abstract Full Text PDF PubMed Google Scholar). Hexameric complexes are recovered on glycerol or sucrose gradients after detergent solubilization (25Chadwick C.C. Goormaghtigh E. Scarborough G.A. A hexameric form of the Neurospora crassa plasma membrane H+-ATPase..Arch. Biochem. Biophys. 1987; 252: 348-356Crossref PubMed Scopus (48) Google Scholar) and have made it possible to produce two-dimensional crystals for structural studies (2Auer M. Scarborough G.A. Kuhlbrandt W. Three-dimensional map of the plasma membrane H+-ATPase in the open conformation..Nature. 1998; 392: 840-843Crossref PubMed Scopus (185) Google Scholar), but there is no clear evidence that such complexes exist in vivo. Even though the ER is not as clearly differentiated in yeast as in many mammalian cells, immunofluorescence and immunoelectron microscopy have revealed two morphologically distinct parts: (i) prominent perinuclear elements, continuous with the outer nuclear membrane, and (ii) peripheral tubules, extending outward through the cytoplasm and concentrated in the region immediately beneath the plasma membrane (26Preuss D. Mulholland J. Kaiser C.A. Orlean P. Albright C. Rose M.D. Robbins P.W. Botstein D. Structure of the yeast endoplasmic reticulum: localization of ER proteins using immunofluorescence and immunoelectron microscopy..Yeast. 1991; 7: 891-911Crossref PubMed Scopus (147) Google Scholar). Both are studded with ribosomes and can be labeled by antibodies against ER markers, and it seems likely that they form a single interconnected network (27Klumperman J. Transport between ER and Golgi..Curr. Opin. Cell Biol. 2000; 12: 445-449Crossref PubMed Scopus (110) Google Scholar). If so, one would like to learn where specific plasma membrane proteins are synthesized within the network and where they are packaged into vesicles for shipment to the Golgi. It would also be useful to know where and how such proteins are screened for proper folding before being allowed to leave the ER. Partial answers to both questions have come from the use of Pma1 H+-ATPase as a model plasma membrane protein. Of nearly 300 site-directed mutations that have been introduced throughout the ATPase, amino acid substitutions at 45 positions have led to defects in biogenesis (Fig. 1) (reviewed in Ref. 1Morsomme P. Slayman C.W. Goffeau A. Mutagenic study of the structure, function, and biogenesis of the yeast plasma membrane H+-ATPase..Biochim. Biophys. Acta. 2000; 1469 (review): 133-157Crossref PubMed Scopus (103) Google Scholar). Most (and perhaps all) of these polypeptides are poorly folded, as evidenced by their abnormal sensitivity to trypsin (12Nakamoto R.K. Verjovski-Almeida S. Allen K.E. Ambesi A. Rao R. Slayman C.W. Substitutions of aspartate 378 in the phosphorylation domain of the yeast PMA1 H+-ATPase disrupt protein folding and biogenesis..J. Biol. Chem. 1998; 273: 7338-7344Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 13DeWitt N.D. Tourinho dos Santos C.F. Allen K.E. Slayman C.W. Phosphorylation region of the yeast plasma membrane H+-ATPase. Role in protein folding and biogenesis..J. Biol. Chem. 1998; 273: 21744-21751Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Confocal and immunoelectron microscopy have shown that such mutations trigger a dramatic proliferation of ER-derived membranes, in which misfolded H+-ATPase accumulates along with standard ER markers such as Kar2p (10Harris S.L. Na S. Zhu X. Seto-Young D. Perlin D.S. Teem J.H. Haber J.E. Dominant lethal mutations in the plasma membrane H+-ATPase gene of Saccharomyces cerevisiae..Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10531-10535Crossref PubMed Scopus (62) Google Scholar, 11Portillo F. Characterization of dominant lethal mutations in the yeast plasma membrane H+-ATPase gene..FEBS Lett. 1997; 402: 136-140Crossref PubMed Scopus (28) Google Scholar, 13DeWitt N.D. Tourinho dos Santos C.F. Allen K.E. Slayman C.W. Phosphorylation region of the yeast plasma membrane H+-ATPase. Role in protein folding and biogenesis..J. Biol. Chem. 1998; 273: 21744-21751Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar,21Kerchove d'Exaerde A. Supply P. Goffeau A. Subcellular traffic of the plasma membrane H+-ATPase in Saccharomyces cerevisiae..Yeast. 1996; 12: 907-916Crossref PubMed Scopus (30) Google Scholar). When wild-type H+-ATPase is co-expressed with a mutant of this type, it becomes arrested in the same membranes and growth stops; thus, the mutation acts genetically in a dominant lethal (10Harris S.L. Na S. Zhu X. Seto-Young D. Perlin D.S. Teem J.H. Haber J.E. Dominant lethal mutations in the plasma membrane H+-ATPase gene of Saccharomyces cerevisiae..Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10531-10535Crossref PubMed Scopus (62) Google Scholar, 11Portillo F. Characterization of dominant lethal mutations in the yeast plasma membrane H+-ATPase gene..FEBS Lett. 1997; 402: 136-140Crossref PubMed Scopus (28) Google Scholar, 12Nakamoto R.K. Verjovski-Almeida S. Allen K.E. Ambesi A. Rao R. Slayman C.W. Substitutions of aspartate 378 in the phosphorylation domain of the yeast PMA1 H+-ATPase disrupt protein folding and biogenesis..J. Biol. Chem. 1998; 273: 7338-7344Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 13DeWitt N.D. Tourinho dos Santos C.F. Allen K.E. Slayman C.W. Phosphorylation region of the yeast plasma membrane H+-ATPase. Role in protein folding and biogenesis..J. Biol. Chem. 1998; 273: 21744-21751Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). experiments have that the of in the ER with the of the pma1 to is residues from the that is by during the The folding defect and is arrested in the it then via the secretory vesicles to the plasma membrane, from which it is to the for N.D. Tourinho dos Santos C.F. Allen K.E. Slayman C.W. Phosphorylation region of the yeast plasma membrane H+-ATPase. Role in protein folding and biogenesis..J. Biol. Chem. 1998; 273: 21744-21751Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Confocal microscopy has shown that the of in ER-derived near the of the A. and C. W. in by the to the known of mammalian cells is and concentrated during export from the endoplasmic 1994; Full Text PDF PubMed Scopus Google Scholar) and to specific exit from the ER. with the of in biogenesis it is not a fully dominant mutation but growth of cells wild-type H+-ATPase N.D. Tourinho dos Santos C.F. Allen K.E. Slayman C.W. Phosphorylation region of the yeast plasma membrane H+-ATPase. Role in protein folding and biogenesis..J. Biol. Chem. 1998; 273: 21744-21751Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). in which the has been by a to a dominant lethal As by its sensitivity to this ATPase is very poorly folded and becomes arrested in which are from the ER (10Harris S.L. Na S. Zhu X. Seto-Young D. Perlin D.S. Teem J.H. Haber J.E. Dominant lethal mutations in the plasma membrane H+-ATPase gene of Saccharomyces cerevisiae..Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10531-10535Crossref PubMed Scopus (62) Google Scholar, 13DeWitt N.D. Tourinho dos Santos C.F. Allen K.E. Slayman C.W. Phosphorylation region of the yeast plasma membrane H+-ATPase. Role in protein folding and biogenesis..J. Biol. Chem. 1998; 273: 21744-21751Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar) and proliferation of the to to the and is into the cytoplasm for by the Q. Chang A. Eps1, a novel PDI-related protein involved in ER quality control in yeast..EMBO J. 1999; 18: 5972-5982Crossref PubMed Scopus (88) Google Scholar). into the of the ER quality control process has come from screening for of the dominant lethal of Q. Chang A. Eps1, a novel PDI-related protein involved in ER quality control in yeast..EMBO J. 1999; 18: 5972-5982Crossref PubMed Scopus (88) Google Scholar). has a gene prevents of the and it to the cell The of the gene to the protein family and as a for misfolded H+-ATPase is not fully but has or no on the biogenesis of the wild-type H+-ATPase or on the of proteins that in the ER. proteins for the plasma membrane are from the ER to the by COPII protein complexes known as and (reviewed in Ref. C. COPII and selective export from the endoplasmic Biophys. Acta. 1998; (review): PubMed Scopus Google Scholar). work has coat that helps to Pma1 ATPase into COPII vesicles (19Roberg K.J. Crotwell M. Espenshade P. Gimeno R. Kaiser C.A. LST1 is a SEC24 homologue used for selective export of the plasma membrane ATPase from the endoplasmic reticulum..J. Cell Biol. 1999; 145: 659-672Crossref PubMed Scopus (130) Google Scholar) (Fig. As by its the LST1 gene found in a for mutations that growth with a mutation in one of the known coat protein of LST1 also lethal in with mutations in or K.J. Crotwell M. Espenshade P. Gimeno R. Kaiser C.A. LST1 is a SEC24 homologue used for selective export of the plasma membrane ATPase from the endoplasmic reticulum..J. Cell Biol. 1999; 145: 659-672Crossref PubMed Scopus (130) Google Scholar). of in which a of mutations to a defect one is known as and can be to a between the Lst1p with Sec24p (19Roberg K.J. Crotwell M. Espenshade P. Gimeno R. Kaiser C.A. LST1 is a SEC24 homologue used for selective export of the plasma membrane ATPase from the endoplasmic reticulum..J. Cell Biol. 1999; 145: 659-672Crossref PubMed Scopus (130) Google Scholar), and it has been from yeast as a Y. Kurihara T. Ravazzola M. Amherdt M. Orci L. Schekman R. Lst1p and Sec24p cooperate in sorting of the plasma membrane ATPase into COPII vesicles in Saccharomyces cerevisiae..J. Cell Biol. 2000; 151: 973-984Crossref PubMed Scopus (116) Google Scholar). a functional there is good evidence that but is not for the of Pma1 ATPase into COPII in transport of the ATPase out of the ER is but not blocked (19Roberg K.J. Crotwell M. Espenshade P. Gimeno R. Kaiser C.A. LST1 is a SEC24 homologue used for selective export of the plasma membrane ATPase from the endoplasmic reticulum..J. Cell Biol. 1999; 145: 659-672Crossref PubMed Scopus (130) Google Scholar). although and can work together to the ATPase in Lst1p can be as as a of Sec24p is Y. Kurihara T. Ravazzola M. Amherdt M. Orci L. Schekman R. Lst1p and Sec24p cooperate in sorting of the plasma membrane ATPase into COPII vesicles in Saccharomyces cerevisiae..J. Cell Biol. 2000; 151: 973-984Crossref PubMed Scopus (116) Google Scholar). on these and et al. Y. Kurihara T. Ravazzola M. Amherdt M. Orci L. Schekman R. Lst1p and Sec24p cooperate in sorting of the plasma membrane ATPase into COPII vesicles in Saccharomyces cerevisiae..J. Cell Biol. 2000; 151: 973-984Crossref PubMed Scopus (116) Google Scholar) have that Pma1 ATPase a sorting that with Sec24p and with Lst1p and to newly synthesized ATPase into ER-derived An model be at the of the of and in mammalian cells, where they form in the and are to a role in membrane trafficking and cell (reviewed in Ref. E. Structure and of and membrane Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). et al. M. S. A. A. in of proteins to the cell surface in Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar) have from yeast cells by as The which as as the ER in the plasma membrane in a of and and has shown to Pma1 ATPase and at one protein a protein of for the cell are proteins and proteins for the and it seems to of as the at which proteins for to the plasma membrane M. S. A. A. in of proteins to the cell surface in Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). Pma1 ATPase and plasma membrane proteins hydrophobic S. An of the role of in protein J. 1995; PubMed Scopus Google Scholar, sorting of proteins to the ER and plasma membrane in yeast..EMBO J. 1997; PubMed Scopus (151) Google Scholar), they into of the found in S. and the 1993; PubMed Scopus Google Scholar). to this there would be no for a sorting on the ATPase the would the to the Y. Kurihara T. Ravazzola M. Amherdt M. Orci L. Schekman R. Lst1p and Sec24p cooperate in sorting of the plasma membrane ATPase into COPII vesicles in Saccharomyces cerevisiae..J. Cell Biol. 2000; 151: 973-984Crossref PubMed Scopus (116) Google Scholar). studies by Chang and have to a quality control which abnormal that have and to the for such two amino acid substitutions in the and at the of and a temperature-sensitive defect in H+-ATPase biogenesis (14Chang A. Fink G.R. Targeting of the yeast plasma membrane [H+]ATPase: a novel gene AST1 prevents mislocalization of the ATPase to the vacuole..J. Cell Biol. 1995; 128: 39-49Crossref PubMed Scopus (94) Google Scholar). is to the plasma membrane and at it is in the approaches have been used to with the of novel components of the In the screening with a a of related genes for ATPase to the pathway and to the plasma membrane (14Chang A. Fink G.R. Targeting of the yeast plasma membrane [H+]ATPase: a novel gene AST1 prevents mislocalization of the ATPase to the vacuole..J. Cell Biol. 1995; 128: 39-49Crossref PubMed Scopus (94) Google Scholar). to be a peripheral membrane which with that to the identified In a screening with to the plasma membrane W. Chang A. Novel genes involved in endosomal traffic in yeast revealed by suppression of a targeting-defective plasma membrane ATPase mutant..J. Cell Biol. 1997; 138: 731-746Crossref PubMed Scopus (91) Google Scholar). of known protein genes that control the biogenesis of newly synthesized are not for biogenesis but have effects on or protein trafficking W. Chang A. Novel genes involved in endosomal traffic in yeast revealed by suppression of a targeting-defective plasma membrane ATPase mutant..J. Cell Biol. 1997; 138: 731-746Crossref PubMed Scopus (91) Google Scholar, 18Luo W. Chang A. An endosome-to-plasma membrane pathway involved in trafficking of a mutant plasma membrane ATPase in yeast..Mol. Biol. Cell. 2000; 11: 579-592Crossref PubMed Scopus (64) Google Scholar). on these which to a and role of the endosomal in the of the mutant the have the of pathway W. Chang A. Novel genes involved in endosomal traffic in yeast revealed by suppression of a targeting-defective plasma membrane ATPase mutant..J. Cell Biol. 1997; 138: 731-746Crossref PubMed Scopus (91) Google Scholar, 18Luo W. Chang A. An endosome-to-plasma membrane pathway involved in trafficking of a mutant plasma membrane ATPase in yeast..Mol. Biol. Cell. 2000; 11: 579-592Crossref PubMed Scopus (64) Google Scholar) (Fig. most cell surface or wild-type H+-ATPase travels from the to the cell surface via secretory which from the to with the plasma In yeast at two of secretory in size but by E. A. secretory to the cell surface in yeast..J. Cell Biol. 1995; PubMed Scopus Google Scholar). The ATPase is found in the major together with the cell form of the such as and acid as as E. A. secretory to the cell surface in yeast..J. Cell Biol. 1995; PubMed Scopus Google Scholar). As there is no clear evidence that the H+-ATPase is active in the although it can be protected from trypsinolysis there by ligands such as and In the secretory the ATPase is clearly to and pump protons at with in the plasma this secretory vesicles to be used as a for site-directed pma1 mutants R.K. Rao R. Slayman C.W. of the yeast plasma membrane [H+]ATPase in secretory a new for Biol. Chem. 1991; Full Text PDF PubMed Google Scholar). Pma1 H+-ATPase with a of it one of the most of the yeast plasma membrane E. R. of the plasma membrane ATPase and its in yeast Biophys. Acta. 1991; PubMed Scopus Google Scholar). the mutant has a of the plasma membrane by of the pathway to in the the of a quality control at the yeast cell The for misfolded H+-ATPase is unknown, but a protein known as has been shown to be for of is a of the and in the of vesicles by at the of (Fig. (reviewed in Ref. traffic in the yeast and sorting Opin. Cell Biol. 1998; PubMed Scopus Google Scholar). Interestingly, mutations in have been by their to the abundance of wild-type ATPase at the cell surface S. Hincapie M. McCusker J.H. Haber J.E. MOP2 (SLA2) affects the abundance of the plasma membrane H+-ATPase of Saccharomyces cerevisiae..J. Biol. Chem. 1995; 270: 6815-6823Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). is evidence that plays role in the of plasma membrane proteins (reviewed in L. and of plasma membrane J. 1997; 11: PubMed Scopus Google and L. with transporters and Cell Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) but it is involved in the of mutant or wild-type H+-ATPase to be the has to the by which a abundant plasma membrane the yeast travels from the ER to the cell work the between the sorting of newly synthesized ATPase into and the of the ATPase into the of COPII The of these within the ER also be of as as the functional role of the that form in pma1 mutants such as In is to the significance of the stepwise phosphorylation that of Pma1 ATPase along the secretory Finally, can as a valuable model for quality control during biogenesis because abnormal are and at successive points along the and of ATPase biogenesis to be active for study in the to on of the P-type ATPase the is to the review of Na+,K+- and by and in sorting and of the Na+,K+- and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). for of this