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Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology

Nature Reviews Molecular Cell Biology volume 8, pages 917–929 (2007)Cite this article

Key Points

  • The vacuolar (V-)ATPases are ATP-driven proton pumps that function to acidify intracellular compartments and transport protons across the plasma membrane. They function in various normal and disease processes, including membrane trafficking, protein degradation, bone resorption and tumour metastasis.

  • V-ATPases are large, multisubunit complexes that are composed of two domains that operate by a rotary mechanism. ATP hydrolysis in the V1 domain drives movement of a central rotary complex that, in turn, results in proton translocation through the integral V0 domain.

  • Assembly of V-ATPases requires a number of dedicated chaperones that reside in the endoplasmic reticulum and that assist in correct assembly of the integral V0 domain. Targeting of V-ATPases to different cellular destinations is controlled by isoforms of subunit a, a 100-kDa subunit of V0.

  • V-ATPase activity is regulated in vivo by a number of mechanisms, including reversible dissociation of the V1 and V0 domains. The assembly status of the V-ATPase is in turn dependent on various effectors, including RAVE (regulator of the ATPase of vacuolar and endosomal membranes), aldolase and the cellular environment.

  • Various cells also control the density of V-ATPases in the plasma membrane as an important part of their physiology, including osteoclasts and renal intercalated cells. Insight into how this is accomplished has recently emerged from studies of epididymal cells in the male reproductive tract.

  • The integral V0 domain of the V-ATPase has been postulated to have a direct role in membrane fusion independently of its effects on acidification. Support for this hypothesis has recently emerged from studies in yeast, Drosophila melanogaster and Caenorhabditis elegans.

Abstract

The acidity of intracellular compartments and the extracellular environment is crucial to various cellular processes, including membrane trafficking, protein degradation, bone resorption and sperm maturation. At the heart of regulating acidity are the vacuolar (V-)ATPases — large, multisubunit complexes that function as ATP-driven proton pumps. Their activity is controlled by regulating the assembly of the V-ATPase complex or by the dynamic regulation of V-ATPase expression on membrane surfaces. The V-ATPases have been implicated in a number of diseases and, coupled with their complex isoform composition, represent attractive and potentially highly specific drug targets.

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Figure 1: Structure of the V-ATPase.
Figure 2: Mechanism of proton transport by the V-ATPase.
Figure 3: Assembly of the V-ATPase complex in yeast.
Figure 4: Regulation of V-ATPase activity.
Figure 5: Role of intracellular V-ATPases in normal and disease processes.

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Acknowledgements

The author thanks S. Bond, D. Cipriano, A. Hinton, K. Jefferies, J. Qi and Y. Wang for many helpful discussions. This work was supported by National Institutes of Health Grant GM34478.

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  1. The Department of Physiology, Tufts University School of Medicine, 136 Harrison Ave., Boston, 02111, Massachusetts, USA

    Michael Forgac

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Glossary

Coupled transport

The coupled movement of two solutes or ions in the same or opposite directions mediated by specific transport proteins. For example, the noradrenaline—proton antiporter is responsible for uptake of noradrenaline into synaptic vesicles coupled to the efflux of protons.

ATP synthase

A Large, multisubunit complex (also called F1F0) that is involved in coupling the synthesis of ATP to the downhill transport of protons in mitochondria, chloroplasts and bacteria.

A-ATPase

An ATPase found exclusively in Archaea that is often involved in ATP synthesis (like the F-ATP synthases). A-ATPases are structurally closer to V-ATPases than to F-ATPases.

Proteolipid

A set of highly hydrophobic V-ATPase subunits (c, c′ and c″) that can be extracted into organic solvents.

Stator

The stationary part of the V-ATPase complex, composed of the A3B3 hexamer, the peripheral stalks and subunits a and e.

Cys-mediated crosslinking

Covalent crosslinking between proteins using either disulphide-bond formation between engineered Cys residues or using engineered Cys residues as the site of attachment of Cys-specific photoactivatable crosslinking reagents, such as maleimidobenzophenone.

Hemi-channels

Aqueous channels in proteins that extend only part way through the membrane.

Osteoclasts

Cells that are involved in bone resorption.

Renal intercalated cells

Renal cells in the late distal tubule and collecting duct that are specialized either for acid secretion (alpha intercalated cells) or bicarbonate secretion (beta intercalated cells). These cells help to regulate the acid–base balance in the kidney.

Epididymal clear cells

Cells that line the epididymis and that maintain the low lumenal pH that is necessary to keep sperm in a dormant state.

Renal proximal tubule cells

Renal cells in the proximal tubule that, among other functions, reabsorb peptides and small proteins that escape the glomerular filtration barrier.

Ubiquitin ligase

Protein complexes that attach ubiquitin to protein substrates for the purpose of degradation by the proteasome.

Aldolase

A glycolytic enzyme that catalyses the cleavage of fructose-1,6-diphosphate to glycrealdehyde-3-phosphate and dihydroxyacetone phosphate.

Distal tubule and collecting duct

Late portions of the renal tubule that include, among other cell types, intercalated cells.

Gelsolin

An actin-binding protein that can sever actin filaments.

Sorting endosome

An early endosomal compartment in which low pH triggers dissociation of internalized ligand—receptor complexes.

Glomerular barrier

The filtration barrier in the glomerulus at one end of the renal tubule across which plasma is filtered. This prevents cells and most proteins from entering the lumen of the renal tubule.

Adaptor protein-2

(AP2). A protein complex that is involved in clathrin-mediated endocytosis from the plasma membrane.

CD4

The major cell-surface receptor involved in infection of cells by HIV.

SNARE

(Soluble N-ethylmaleimide-sensitive factor attachment protein receptor). A family of coiled-coil proteins that are present on adjacent membranes and that are thought to assist in vesicle docking and membrane fusion through the formation of trans-SNARE complexes that bridge two membranes.

Cathepsin

Protease that normally resides in lysosomes but that can be secreted by cells that require a low pH for their activity.

Left–right asymmetry

The phenomena whereby some visceral organs are asymmetrically distributed on the left or right side of the organism.

Osteoporosis

A disease that is characterized by loss of bone density.

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Forgac, M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol 8, 917–929 (2007). https://doi.org/10.1038/nrm2272

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