Physiology 21: 317-325, 2006;
doi:10.1152/physiol.00017.2006
1548-9213/06 $8.00
Physiology, Vol. 21, No. 5, 317-325,
October 2006
© 2006 Int. Union Physiol. Sci./Am. Physiol. Soc.
REVIEW
The Emerging Structure of Vacuolar ATPases
Omri Drory and
Nathan Nelson
Department of Biochemistry, The George S. Wise Faculty of Life Sciences, The Daniella Rich Institute for Structural Biology, Tel Aviv University, Tel Aviv, Israel, nelson{at}post.tau.ac.il
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Abstract
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Bioenergetics and physiology of primary pumps have been revitalized by new insights into the mechanism of energizing biomembranes. Structural information is becoming available, and the three-dimensional structure of F-ATPase is being resolved. The growing understanding of the fundamental mechanism of energy coupling may revolutionize our view of biological processes. The F- and V-ATPases (vacuolar-type ATPase) exhibit a common mechanical design in which nucleotide-binding on the catalytic sector, through a cycle of conformation changes, drives the transmembrane passage of protons by turning a membrane-embedded rotor. This motor can run in forward or reverse directions, hydrolyzing ATP as it pumps protons uphill or creating ATP as protons flow downhill. In contrast to F-ATPases, whose primary function in eukaryotic cells is to form ATP at the expense of the proton-motive force (pmf), V-ATPases function exclusively as an ATP-dependent proton pump. The pmf generated by V-ATPases in organelles and membranes of eukaryotic cells is utilized as a driving force for numerous secondary transport processes. V- and F-ATPases have similar structure and mechanism of action, and several of their subunits evolved from common ancestors. Electron microscopy studies of V-ATPase revealed its general structure at low resolution. Recently, several structures of V-ATPase subunits, solved by X-ray crystallography with atomic resolution, were published. This, together with electron microscopy low-resolution maps of the whole complex, and biochemistry cross-linking experiments, allows construction of a structural model for a part of the complex that may be used as a working hypothesis for future research.
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Introduction
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Vacuolar ATPase (V-ATPase) is a multi-subunit complex found in all eukaryotic cells that is responsible for the acidification of intracellular compartments. These compartments include endosomes, lysosomes, Golgi membranes, clathrin-coated vesicles, several types of secretory granules, and the central vacuoles of plants and yeast (48, 53, 62). Each of these intracellular compartments has a specific requirement for the internal pH that is generated by the V-ATPase function (23, 52). In addition to pumping protons into the various organelles, the V-ATPase complex may also participate in sensing their internal pH (28, 58). In a single cell, V-ATPases can be involved in a variety of essential cellular functions, including receptor-mediated endocyto-sis, posttranslational modification, protein sorting along the secretory pathway, protein degradation, and secondary transport (28, 62).
The general structure of F-ATPase (ATP synthase) and V-ATPases is quite similar, and they may share a common mechanism of action that involves mechanochemical energy transduction (48). Both holoenzymes are composed of catalytic sectors, F1 and V1, respectively, and membrane sectors, Fo and Vo, respectively. Although it is assumed that a similar mechanism underlies ATP-dependent proton pumping by F- and V-ATPases in eukaryotic cells, the latter cannot catalyze pmf-driven ATP synthesis. The loss of this ability is perhaps due to a proton slip that is a consequence of alterations in the membrane sector (52). The major events that make V-ATPase unique include gene duplication of the proteolipids and the presence of three distinct proteolipids in each complex. V0 (sub-units a, d, and e and the proteolipids subunits c, c', and c'') and V1 (subunits A and B) are connected by a pro-tein shaft (subunits D and F). The shaft transfers the energy of ATP hydrolysis to the movement of the prote-olipids ring. This movement is relative to the proton channel at subunit a that drives the proton pumping against the concentration gradient. The two sectors are held together by a stator composed of the membrane-anchored subunit b in F-ATPase and subunits E and G in V-ATPase (Table 1
, FIGURE 1).
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FIGURE 1. Schematic model of yeast V-ATPase: moving and static parts
The moving parts are colored in red; the static parts are shown in blue. All the different subunits are denoted as spheres with arbitrary size.
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Although the function of the F-ATPase homologous subunits could be easily suggested, V-ATPase has several unique subunits: subunits d, C, and H. These nonhomologous subunits may be responsible for the unique V-ATPase properties. Subunit d (Vma6p) is a unique V-ATPase subunit that was found to be peripherally attached to the cytoplasmic face of the membrane sector (9, 48, 62, 69). Both subunits H and C are present only in eukaryotic V-ATPases. Subunit H (Vma13p) is required for the activity of the enzyme, but the other subunits could be assembled in its absence, suggesting a regulatory function (59). Subunit C (Vma5p) is required for proper assembly of the V-ATPase (9, 14, 34). It has been shown that this subunit has actin- and nucleotide-binding properties (6, 14, 68). Furthermore, it is the only subunit that reversibly leaves the enzyme in glucose deprivation, causing the catalytic subcomplex to detach from the membrane sector (14). This suggests that it acts as part of the stator.
During the last few years, structural information was accumulated on V-ATPase and prokaryotic V-ATPase homologs, which, with additional biochemical, genetic, and electron microscopy data, opened the opportunity to construct a working model for the complete V-ATPase complex.
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Crystal Structure of Eukaryotic V-ATPase Subunits
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In 1994, Boyer’s binding change mechanism (12, 13) was proved with the release of the first high-resolution X-ray crystallography structure of the F-ATPase F1 sub-complex from bovine heart mitochondria (1). Since then, only two high-resolution structures of eukaryot-ic V-ATPase (Sachromyces cerevisiae) became available (17, 18, 60). These subunits (C and H) are the last to be assembled into the holoenzyme (48, 65, 66). A few other structures of V-type ATPase subunits of prokaryotes had been published (FIGURE 2; Refs. 31, 44, 61). These could be utilized for constructing a model for the eukaryotic enzyme.
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Yeast V-ATPase Subunit H
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Subunit H was first found as a band on SDS gels that migrated just below subunit B from a purified preparation of V-ATPases from various sources (22, 39, 56). The yeast gene was cloned, and a null mutant was prepared. The mutant gave similar conditional lethal phenotype to other V-ATPase null mutants: the ability to grow at low pH (5.5) but not on neutral pH (27, 50). Biochemical studies showed that the other V-ATPase subunits were able to assemble into the full complex, which had no ATP hydrolysis or proton-pumping activities (27). This observation and others led to the assignment of a regulatory function for the V-ATPase catalytic activity. Furthermore, it has been shown that subunit H interacts with several other proteins: HIV-Nef (21, 40) and ecto-apyrase (74). It was the first eukaryotic V-ATPase subunit to be crystallized, and its structure was determined at 2.95-Å resolution (60). Subunit H is an all alpha helical structure composed of two distinct domains: the NH2-terminal domain (amino acids 2–352) and a smaller COOH-terminal domain (amino acids 353–478). The NH2-terminal domain has five HEAT or an armadillo repeat fold, which is the hallmark of the importin family. The importin family import proteins that contain NLS (nuclear localization signal) to the nucleolus. The groove that binds the NLS in importins is occupied in subunit H by its own 10 amino acid starch in the NH2-terminal. The COOH-terminal domain is connected by a short, probably flexible loop, has eight alpha helices, and a similar arrangement and fold as the NH2 termini but is less ordered (FIGURE 2B
). Expression ofthe NH2-terminal domain, but not the COOH-terminal domain, in yeast vma13 null mutants partially complements the growth defects of the mutant (38). Expression of both domains gave better complementation than either fragment alone.
The structure of subunit H suggests interaction with nuclear components. This is one of several features that distinguish V-ATPase from F-ATPase, which is confined to the interior of the semiautonomous organelle chloroplasts or mitochondria and is precluded from interaction with cytoplasmic components.
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Yeast V-ATPase Subunit C
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The cDNA encoding subunit C was first cloned from bovine’s adrenal medulla (47, 51). Subsequently, the yeast gene (VMA5) was cloned, and a null mutant, with a typical V-ATPase conditional lethal phenotype, was constructed (9). In this mutant, both V1 and V0 subcomplexes were assembled without binding together to form the full active complex (15, 26). The yeast subunit C is the only subunit that reversibly leaves the enzyme in glucose deprivation, causing the catalytic subcomplex to detach from the membrane sector (14). This suggests that it is part of the peripheral stator of V-ATPase. In addition, it was shown to have actin-binding activity (68) and may undergo structural changes by ADP binding (6, 19). The crystal structure of the yeast V-ATPase subunit C (Vma5p) was recently solved at 1.75-Å resolution (18). It was showed to be composed of three distinct domains: "head" and "foot" that are connected by a flexible elongated "neck" (FIGURE 2C). The foot domain is composed of four anti-parallel beta strands and two short alpha helices in a globular fold formed by the NH2 and COOH terminals. The head domain (amino acids 166–263) has the same structural fold as the foot domain of four anti-parallel beta strands and two short alpha helices, even though there was no obvious sequence homology. The elongated neck domain (amino acids 49–165 and 264–323) is composed of two 80-Å-long alpha helices and a shorter 48-Å-long helix in an alpha helical bundle fold. Vma5p was crystallized in two crystal forms (18): a tetragonal crystal, which diffracted to 1.75 Å, and trigonal crystals, which diffracted to 2.9 Å. The two crystal structures share the same foot and lower neck domain orientations, but the head and the upper neck domains had different conformations. This elastic movement of the head domain was suggested to have a functional role in the smooth coupling of torque energy between the V1 and V0 subcomplexes as part of its stator function.
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Crystal Structure of F-ATPase F1 Subcomplex
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A major breakthrough in the understanding of F-ATPase function was achieved with the elucidation of the structure of bovine’s heart mitochondria F-ATPase F1 sector in 1994 (1). This crystal structure, at 2.8-Å res-olution, of the AMP-PNP-inhibited state of the F1 sec-tor revealed a molecule consisting of alternating 
and ß subunits in a 3/3ß complex that creates a ring structure. The NH2 terminus of the elongated helical subunit 
protrudes to the shaft created by the ring structure, whereas its COOH terminus stretches 45 Å away from the 3/3ß complex. The structure and location of subunit were found in following structural studies. The subunits 
and are bounded, forming a 3 foot-like structure that connects to the c ring of the F0 part (Ref. 63; FIGURE 2A). Three catalytic sites were observed in the 3/3ß complex that varies depending on the nucleotide occupancy: empty, with ADP, or with AMP-PNP (or "open," "loose," and "tight" sites, respectively). Those structural features of 3/3ß complex supported the rotational catalysis mechanism and were in agreement with Boyer’s hypothesis of the binding change mechanism (12, 13).
The F-ATPase F1 subcomplex known structure was utilized as a homolog of V-ATPase V1 subcomplex for the model (FIGURE 4).
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Crystal Structure of Prokaryotic V-ATPase Subunits
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The ATP-synthase of archaea (A-ATPase) is essentially a chimeric complex, where the catalytic subunits A and B are closely related to the corresponding V-ATPase subunits, and the proteolipids are similar to the F-ATPase c subunits in their size, assembly, and function (45, 46). Even though ATP-synthases of the F-and A-type are predicted to have similar if not identical mechanism of ATP-dependent proton uptake, major differences were recently discovered (29). In A-ATPase (V-type) of Thermus thermophilus, at low ATP concentrations, the D subunit rotated stepwise, pausing every 120 degrees, and it consumes one ATP per step. It is in contrast to F-ATPase, which cleaves one ATP at 80 degrees posterior to the binding of ATP. Although A-ATPase generates a torque of 35 pN·nm, F-ATPase generates a torque of 46 pN·nm. This finding suggests that the mechanism of ATP-dependent proton uptake by eukaryotic V-ATPase will be quite different from F-ATPase and even its relative A-ATPase.
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Structure of Subunit B of the Archaea Methanosarcina Mazei
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Subunits A of A- and V-ATPases contain sequences of the canonical ATP-binding site just as the ß subunit of F-ATPase. Subunit B of A- and V-ATPases do not have the consensus GxxGxGKT/S that is the phosphate binding P-loop present in F-ATPase catalytic subunits. Thus the function of ATP binding demonstrated for B subunits is not clear. Recently, subunit B of the archaea M. mazei was expressed, crystallized, and solved at 1.5-Å resolution (61). Superposition of the B subunit of A-ATPase and the subunit of F-ATPase provided new insights into the similarities and differences between these two subunits. The overall structure of subunit B is similar to that of the related noncatalytic subunit of F-ATPase (1, 61). Remarkably, even though their sequence identity is only 25%, both subunits superimpose with root mean square deviation of 1.85 Å. Subunit B of M. mazei is about 60% identical to the corresponding subunit B in V-ATPases, and it is likely that it will closely represent the subunit structure. Yet the published structure reveals no further information on the possible rotary mechanism of ATP-dependent proton uptake by eukaryotic V-ATPases.
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The Structure of NtpK K Subunit that is Homologous to Subunit c, c', and c'' of Eukaryotic V-ATPase
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Subunit c (proteolipid) of V-ATPase was first identified and cloned from bovine’s adrenal medullas (41). The yeast gene (VMA3) was subsequently cloned, and a null mutant was constructed. It showed a typical V-ATPase conditional lethal phenotype (49, 50, 67). The V-type ATPase c subunit (16 kDa) is twice as large as the equivalent F-type ATPase proteolipid subunit (8 kDa) and has twice as much transmembrane helices. It is thought to be evolved from gene duplication and fusion events from an ancestral 8-kDa proteolipid (45, 46, 49). Subsequently, two other homologous proteins were found in the yeast genome (VMA11 and VMA16) and their gene products were denoted as c' and c'' (25). Similar genes were found in C. elegans, mammals, and plants (7, 55). The yeast deletion mutants in these subunits share the same V-ATPase null-mutant phenotype. This observation was supported by substitution of the critical glutamate residue at the proton binding pocket, which resulted in properly assembled but not active complex (25, 54). It was proposed that the three different proteolipid subunits in eukaryotic V-ATPase were evolved by the need to change the coupling efficiency of V-ATPases by a "slip" mechanism (52).
The eubacteria Enterococcus hirae has a V-type sodium ATPase (NtpK) that exhibits a significant homology to the eukaryotic V-ATPase in most of its subunits (43). Recently, its rotor ring that is composed of 10 c subunits, each of four transmembrane helices, was crystallized and solved to 2.1-Å resolution (44). Simultaneously, the crystal structure of F-type sodium ATPase from Ilyobacter tartaricus was solved to 2.4-Å resolution (42). Remarkably, despite the fact that it is half the size of the NtpK ring (the subunits are composed of only two transmembrane helices), its rotor ring is composed of 10 proteolipids as well. Thus the rotor ring of NtpK has a significantly larger diameter, but since each c subunit binds one sodium ion, the stoichiometry of ATP/Na is identical in the two enzymes (33). The sodium binding sites of the NtpK rotor ring are located in a pocket deeply embedded in the membrane, formed between helix H2 and H4 (FIGURE 2D). This pocket includes the conserved and essential amino acids that are present in all V-type ATPases. The high resolution that was obtained provided the possibility to fit bound lipids and detergent molecules, which are situated in both the middle hollow part of the ring and outside facing the membrane.
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T. Thermophilus Subunit C Structure
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The A-ATPase of T. thermophilus contains a subunit that unfortunately is denoted as subunit C but is not homologous, analogous, or structurally related to the C subunit of eukaryotic V-ATPase (18, 73). Recently, the structure of this protein was solved to 1.95-Å resolution (31). The crystal structure revealed an all alpha helical, threefold symmetry, funnel-shape fold with dimensions of 45 x 50 x 50 Å (FIGURE 2E). This subunit co-purified with the membrane sector and was shown to cross-link to the proteolipid ring subunit L, which is the T. thermophilus homolog of eukaryotic V-ATPase subunit c proteolipid (73). This bacterial subunit C has very low (if any) sequence homology to the eukaryotic V-ATPase subunit d; however, it was suggested to function similarly (31). Subunit d was initially cloned from bovine’s adrenal medulla (69). The yeast gene encoding this subunit (VMA6) was cloned, and a null mutant was constructed (8). The vma6 null mutants exhibited identical properties compared with the other V-ATPase null mutants, and V1 failed to associate with V0. These findings suggested a possible function in linking the two parts of the enzyme. Subunit d is part of the V0 sector, but since it is not an integral membrane protein it is peripherally associated with the V0 sector on the cytosolic side of the membrane.
The structure of the T. thermophilus enzyme has a polar cavity open to one side and a polar surface with no apparent hydrophobic anchor to the membrane sector. The structure consists of three distinct domains related by a nonperfect threefold symmetry, suggesting gene triplication (even though there is no obvious sequence homology). Each domain is composed of two central 50-Å-long and four 25-Å-long peripheral helices. The central helices create the central cavity, which has a remarkable fitting to the cavity at the cytoplasmic face of the L (or c) ring. This observation was supported by a site-directed mutagenesis and cys-teine-mediated chemical cross-linking (31).
The question as to whether T. thermophilus subunit C is structurally, and functionally, related to V-ATPase subunit d remains open, but, as frequently happens, highly resolved structures easily capture our imagination. Therefore, for the time being, the notion that T. thermophilus subunit C is homologous to subunit D of V-ATPase and fitted its structure is adopted for the model presented in this review.
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Subunit Interactions in V-ATPase
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The connection between subunits in the V-ATPase complex was studied by a variety of methods: binding assays, yeast two hybrid system, and chemical cross-linking. A summary of the published observations is given in Table 2. Knowledge of the overall structure of V-ATPase and especially high-resolution structure of individual subunits allowed the construction of sensible mutations. Insertions of cysteine residues in structurally defied sites and performance of cysteine-mediated cross-linking have recently helped to locate those areas in subunit C that interact with subunits E and G (30). This data was used for the construction of a working model depicted in FIGURE 3. Each of the methods used for the study of subunit interactions might give erroneous results. Although there is no replacement for straight-forward structural data, while awaiting the crystal structure of V-ATPase, one must resort to other methods that provide relatively low-resolution structural data.
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FIGURE 3. Interaction between V-ATPase subunits
The interactions were implied from cross-linking, yeast two hybrid experiments, and binding assays. The interaction data are summarized in Table 2 and depicted as arrows. The structures were colored as in Figure 1. Unknown structures of subunits E, G, and A are shown as spheres colored blue, cyan, and green, respectively.
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Electron Microscopy Studies
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Electron microscopy (EM) was successfully used for obtaining low-resolution structures of macromolecules and protein complexes. Resolution better than 10 Å may be obtained by single-molecule cryo-electron microscopy, especially if high symmetry objects are studied (10). The first electron microscopy images of the V-ATPase revealed a two-sector shape that closely resembled the overall structure of the well-described F-ATPase (11). An excellent review on the structure of V-ATPases revealed by EM was published recently (71). The EM structures from bovine brain (70), insects (59), yeast (75), and plants (37) have been presented, and all share the same structural motifs. The EM maps (16, 31, 70) were used to dock the high-resolution structures of V-ATPase and its homologs, which adds more restraints to the cross-linking experiments and other protein-protein interaction assays when one attempts to construct a structural model. Furthermore, by a differential imaging of a complex with and without subunit h, its precise location in the complex was determined (70). The model suggested in this review utilized the published EM structure of yeast V-ATPase. Direct docking of the suggested model to EM electron density maps is hard to accomplish due to the absence of EM electron density map data files.
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Conclusions and Future Directions
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A model of V-ATPase structure, based on known X-ray structures of V-ATPase subunits and homologs, and information on subunit interactions observed by different biochemical methods was presented. The model illustrates the overall dimensions of this complex and the subunit interactions within it. Only two subunits (C and H) have been solved so far from the yeast V-ATPase. Interestingly, both subunits assemble at the last stage of the complex formation, since one can purify large assemblies of V-ATPase subcomplex in the absence of those subunits. This fact suggests that both subunits should be stable monomers in vivo, which facilitate their ability to crystallize. All other subunits, except subunit C of thormophilus (homologs to subunit d of eukaryotic V-ATPase), were solved as a complex with other subunits, and some of them seemed to be unstable as monomers. In contrast to the F-ATPases, which can be purified in abundance from mitochondria, chloroplast, or bacteria, there is no good source for V-ATPase complex. To overcome this problem, single V-ATPase subunits were expressed in E. coli. This approach yielded the first two eukaryotic V-ATPase structures. Not all the yeast V-ATPase subunits could be readily expressed or, even if large amounts of highly purified protein were obtained, crystallized. Two approaches are accessible: first, co-expression and co-crystallization of V-ATPase subunits in E. coli, which are known to form stable intermediate subcomplexes (E and G, A and B, D and F, A+B+D+F, and more combinations). The second approach is purification of the native or the separate sectors of V-ATPase from the available sources. This is not an easy path to follow, but this road could hopefully yield a complete structural model for this important enzyme.
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Acknowledgments
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This project has been funded by the Bundesministerium für Bildung und Forschung (BMBF) (German Federal Ministry of Education and Research) and supported by BMBF’s international bureau at the DLR (German Aerospace Center).
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Introduction
Crystal Structure of Eukaryotic...
