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J. Biol. Chem., Vol. 276, Issue 32, 29613-29616, August 10, 2001
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,From the Departments of Genetics and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510
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
INTRODUCTION
-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
Ca2+-ATPases, gastric mucosal H+,
K+-ATPase, and sarcoplasmic reticulum
Ca2+-ATPase.
View larger version (30K):
[in a new window]
Fig. 1.
Topology of the yeast plasma membrane
H+-ATPase, based on two- and three-dimensional
crystallography of related ATPases at resolutions of 8 Å (2-4) and
2.6 Å (5). N and C termini are located in the cytoplasm.
Zig-zag lines represent regions predicted to have
-helical secondary structure; red circles mark
positions at which mutations have been found to disrupt protein
folding, block biogenesis, and/or lead to a dominant lethal phenotype
(see text).
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
ER1 (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).
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H+-ATPase Is Made in Rough ER and Delivered to Plasma Membrane via Secretory Pathway |
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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 (22). 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) (8, 9). 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 (9). 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 (9).
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The oligomeric state of the mature H+-ATPase is not yet
certain. Monomers of the closely related Neurospora crassa
enzyme are fully active after reconstitution into proteoliposomes (23), but radiation inactivation experiments give a target size of 230 kDa,
consistent with a functional dimer (24). Hexameric complexes are
recovered on glycerol or sucrose gradients after detergent solubilization (25) and have made it possible to produce
two-dimensional crystals for structural studies (2), but there is no
clear evidence that such complexes exist in vivo.
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Misfolded H+-ATPase Mutants Serve as Markers for Specialized ER Subdomains |
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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 (26). 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 (27). 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. 1). Most (and perhaps all) of these polypeptides are poorly folded, as evidenced by their abnormal sensitivity to trypsin (12, 13). 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 (10, 11, 13, 21). 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 fashion (10-13).
Recent experiments have suggested that the exact point of arrest in the ER may vary with the severity of the pma1 mutation. Least seriously affected among those studied to date is G381A, only three residues downstream from the critical Asp that is phosphorylated by ATP during the catalytic cycle. The G381A polypeptide displays an intermediate folding defect and is transiently arrested in the ER; it then escapes via the secretory vesicles to the plasma membrane, from which it is recycled to the vacuole for degradation (13). Confocal microscopy has shown that the temporary arrest of G381A occurs in punctate ER-derived bodies, located predominantly near the periphery of the cell.2 Upon closer examination by electron microscopy, the punctate bodies look markedly similar to the well known vesicular-tubular compartment of mammalian cells (28) and may therefore correspond to specific exit sites from the ER. Consistent with the intermediate behavior of G381A in biogenesis experiments, it is not a fully dominant mutation but instead allows slow growth of cells co-expressing wild-type H+-ATPase (13).
D378N, in which the catalytically important Asp residue has been
replaced by Asn, exhibits a more severe biogenetic defect, leading to a
dominant lethal phenotype. As judged by its extreme sensitivity to
trypsin, this ATPase is very poorly folded and becomes arrested in
invasive "sausage-like" structures, which are derived from the ER
(10, 13) and may represent proliferation of the vesicular-tubular
elements. Unlike G381A, D378N fails to escape to the Golgi and is
translocated back into the cytoplasm for degradation by the proteasome
(17). Insight into the nature of the ER quality control process has
come from screening an insertional genomic library for suppressors of
the dominant lethal behavior of D378N (17). This approach has yielded a
gene called EPS1 (ER-retained
pma1 suppressing) that, when
disrupted, prevents degradation of the D378N polypeptide and allows it
to reach the cell surface. The product of the EPS1 gene
belongs to the protein disulfide isomerase family and may act as a
membrane-bound chaperone. Its specificity for misfolded
H+-ATPase is not fully understood, but deleting
EPS1 has little or no effect on the biogenesis of the
wild-type H+-ATPase or on the retention of other proteins
that normally reside in the ER.
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Newly Identified Coat Protein (Lst1p) Helps to Package Newly Synthesized H+-ATPase into COPII Vesicles for ER to Golgi Transport |
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Like secreted proteins, proteins destined for the plasma membrane are carried from the ER to the Golgi by COPII vesicles, whose coats contain heterodimeric protein complexes known as Sec23/24p and Sec13/31p (reviewed in Ref. 29). Recent work has turned up another coat component (Lst1p) that helps to package Pma1 ATPase into COPII vesicles (19) (Fig. 2). As suggested by its name (lethal with sec thirteen), the LST1 gene was found in a screen for mutations that block growth when combined with a mutation in one of the known coat protein genes, SEC13. Deletions of LST1 were also lethal in combination with mutations in SEC23, SEC24, or SEC31 (19). This kind of genetic behavior, in which a pair of mutations leads to a more severe defect than either one alone, is known as "synthetic lethality" and can frequently be traced to a physical interaction between the corresponding proteins. Indeed, Lst1p shares 23% sequence identity with Sec24p (19), and it has recently been purified from yeast lysates as a Sec23/Lst1p heterodimer (20).
At a functional level, there is good evidence that Sec23/Lst1p mediates
but is not absolutely required for the recruitment of Pma1 ATPase into
COPII vesicles. Thus, in an lst1 deletion mutant, transport
of the ATPase out of the ER is inhibited but not completely blocked
(19). Furthermore, although Sec23/Lst1p and Sec23/24p can work together
to package the ATPase in vitro, Lst1p can be eliminated as
long as a 10-fold excess of Sec24p is present (20). Based on these and
other results, Shimoni et al. (20) have suggested that Pma1
ATPase may contain a cytoplasmically exposed sorting signal that
interacts weakly with Sec24p and more strongly with Lst1p and serves to
direct newly synthesized ATPase into ER-derived vesicles. An
alternative model will be discussed at the end of the next section.
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Lipid Rafts Help to Carry H+-ATPase through Golgi to Plasma Membrane |
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Lipid rafts, consisting of tightly packed sphingolipids and cholesterol, were first observed in mammalian cells, where they form in the Golgi and are believed to play a role in membrane trafficking and cell signaling (reviewed in Ref. 30). Recently, Bagnat et al. (31) have isolated lipid rafts from yeast cells by flotation as detergent-insoluble glycolipid-enriched complexes. The rafts, which appear as early as the ER in yeast, resemble the plasma membrane in having a high content of sphingolipids, ergosterol, and saturated phospholipids; and mass spectrometry has shown them to contain Pma1 ATPase and at least one other protein (Gas1p, a glycophospholipid-anchored protein of unknown function) bound for the cell surface. Conspicuously absent are ER-resident proteins and proteins destined for the sphingolipid- and ergosterol-poor vacuolar membrane. Thus, it seems reasonable to think of lipid rafts as the point at which proteins accumulate for delivery to the plasma membrane (31).
Because Pma1 ATPase and other plasma membrane proteins possess
relatively long hydrophobic transmembrane segments (32, 33), they may
sort spontaneously into thick bilayers of the kind found in lipid rafts
(34). According to this model, there would be no need for a
cytoplasmically exposed sorting signal on the ATPase itself; rather,
the Sec23/Lst1p heterodimer would somehow tailor the budding vesicle to
accommodate the bulky lipid raft (20).
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Mutant H+-ATPases That Escape ER Undergo a Second Quality Control Step in Golgi |
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Recent studies by Chang and co-workers have pointed to a Golgi-based quality control process, which recognizes abnormal H+-ATPases that have avoided proteasomal degradation and delivers them to the vacuole for proteolysis. One such mutant, pma1-7, carries two amino acid substitutions (P434A in the central cytoplasmic loop and G789S at the extracytoplasmic end of transmembrane segment 8) and displays a temperature-sensitive defect in H+-ATPase biogenesis (14). At 25 °C, Pma1-7p is able to reach the plasma membrane and support growth, whereas at 37 °C, it is degraded rapidly in the vacuole.
Two different approaches have been used to isolate suppressors of pma1-7 with the aim of uncovering novel components of the vacuolar degradation pathway. In the first, screening with a high-copy genomic library yielded a pair of related genes (AST1 and AST2, for ATPase stabilizing) whose products, when overexpressed, cause Pma1-7p to bypass the degradation pathway and travel to the plasma membrane (14). Further examination showed Ast1p to be a peripheral membrane protein, which co-fractionates with detergent-insoluble material that may correspond to the recently identified lipid rafts (see above).
In a subsequent study, screening with an insertional library yielded 16 different SOP (suppressors of
pma1-7) genes, which, when disrupted, could
re-route Pma1-7p to the plasma membrane (16). Eight of the
SOP suppressors match known VPS
(vacuolar protein sorting) genes
that control the biogenesis of newly synthesized vacuolar proteins;
others are not absolutely required for vacuolar biogenesis but still
have noticeable effects on Golgi-to-endosome or endosome-to-vacuole
protein trafficking (16, 18). Based on these results, which point to a
central and complex role of the endosomal system in dictating the fate
of the mutant Pma1-7 H+-ATPase, the authors have proposed
the existence of an alternative endosome-to-surface pathway (16, 18)
(Fig. 2).
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By the Time H+-ATPase Reaches Secretory Vesicles, It Is Capable of ATP-dependent Proton Translocation |
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Like most other cell surface or secreted proteins, wild-type H+-ATPase travels from the Golgi to the cell surface via secretory vesicles, which bud from the Golgi to fuse with the plasma membrane. In fact, yeast contains at least two subpopulations of secretory vesicles, similar in size (100 nm) but separable by equilibrium isodensity sedimentation (35). The ATPase is found in the major vesicle population, together with the cell wall form of endoglucanase (Bgl2p); the minor vesicle population contains periplasmic enzymes such as invertase and acid phosphatase, as well as secreted exoglucanase (Exg1p) (35).
As described above, there is no clear evidence that the
H+-ATPase is catalytically active in the ER, although it
can be protected from trypsinolysis there by ligands such as MgADP and
orthovanadate. In the secretory vesicles, however, the ATPase is
clearly able to hydrolyze ATP and pump protons at rates comparable with
those seen in the plasma membrane; this property allows isolated
secretory vesicles to be used as a convenient expression system for
site-directed pma1 mutants (36).
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Abnormal H+-ATPases That Reach Plasma Membrane Are Retrieved by Endocytosis and Sent to Vacuole for Degradation |
|---|
Wild-type Pma1 H+-ATPase turns over with a half-life
of 11 h, making it one of the most stable constituents of the
yeast plasma membrane (37). By contrast, the G381A mutant polypeptide
has a half-life of only 1 h, leaving the plasma membrane by way of the endocytic pathway to undergo degradation in the
vacuole.2 This finding suggests the
existence of a third quality control mechanism at the yeast cell
surface. The precise mechanism for recognizing misfolded
H+-ATPase is unknown, but a protein known variously as
End4p/Sla2p/Mop2p has been shown to be required for efficient
endocytosis of G381A.2 End4p/Sla2p/Mop2p is a
component of the actin cytoskeleton and may help in the formation of
endocytic vesicles by stimulating actin depolymerization at the site of
vesicle budding (Fig. 2) (reviewed in Ref. 38). Interestingly,
mutations in the END4/SLA2/MOP2 gene have been selected by their ability to lower the abundance of
wild-type ATPase at the cell surface (15). There is considerable evidence that ubiquitination plays an essential role in the endocytosis of short-lived plasma membrane proteins (reviewed in Refs. 39 and 40)
but whether it is similarly involved in the endocytosis of mutant or
wild-type H+-ATPase remains to be established.
| |
Summary and Prospects for Future Work |
|---|
Taken together, the research described above has begun to define
the path by which a highly abundant plasma membrane protein, the yeast
H+-ATPase, travels from the ER to the cell surface. Further
work should clarify the relationship between the sorting of newly
synthesized ATPase into lipid rafts and the packaging of the ATPase
into the appropriate subset of COPII vesicles. The location of these
events within the ER will also be of interest, as well as the
functional role of the exaggerated vesicular-tubular elements that form
in pma1 mutants such as G381A. In parallel, further research
is needed to understand the significance of the stepwise
phosphorylation events that accompany movement of Pma1 ATPase along the
secretory pathway. Finally, Pma1p can serve as a valuable model for
understanding quality control during biogenesis because abnormal forms
are recognized and removed at three successive points along the
pathway. These and other aspects of ATPase biogenesis promise to be
active subjects for study in the years to come. For further information
on members of the P-type ATPase family, the reader is directed to the
accompanying review of Na+,K+- and
H+,K+-ATPases by Dunbar and Caplan (41).
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ACKNOWLEDGEMENT |
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We thank Dr. Michael Caplan for critical reading of this manuscript.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. This is the first article of two in the "Transport ATPase Trafficking Minireview Series."
Present address: Université de Poitiers, Faculté des
Sciences, Laboratoire de Génétique de la Levure, ESA 6161, IBMIG, 40 Avenue du Recteur Pineau, 86022 Poitiers cedex, France.
§ To whom correspondence should be addressed. Tel.: 203-737-1770; Fax: 203-785-7227; E-mail: carolyn.slayman@yale.edu.
Published, JBC Papers in Press, June 12, 2001, DOI 10.1074/jbc.R100022200
2 T. Ferreira, A. B. Mason, and C. W. Slayman, manuscript in preparation.
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ABBREVIATIONS |
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The abbreviation used is: ER, endoplasmic reticulum.
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REFERENCES |
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T. Ferreira, A. B. Mason, M. Pypaert, K. E. Allen, and C. W. Slayman Quality Control in the Yeast Secretory Pathway. A MISFOLDED PMA1 H+-ATPase REVEALS TWO CHECKPOINTS J. Biol. Chem., May 31, 2002; 277(23): 21027 - 21040. [Abstract] [Full Text] [PDF]
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INTRODUCTION
H+-ATPase Is Made in...