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The vacuolar (H+)-ATPases — nature's most versatile proton pumps

Nature Reviews Molecular Cell Biology volume 3, pages 94–103 (2002)Cite this article

Key Points

  • The V-ATPases are composed of a peripheral domain (V1), which is responsible for ATP hydrolysis, and an integral domain (V0), which is responsible for proton translocation. Electron microscopy has shown the existence of multiple stalks that connect V1 and V0.

  • V-ATPases have an important role in various membrane-transport processes, including both endocytosis and intracellular transport. Moreover, the integral V0 domain has recently been proposed to have a direct role in membrane fusion.

  • V-ATPases in the plasma membrane of specialized cells function in processes such as renal acidification and bone resorption. Several genetic diseases have now been traced to defects in genes that encode V-ATPase subunits, including renal tubular acidosis and osteopetrosis.

  • The V-ATPases resemble the F-ATPases, which normally function in ATP synthesis, and are believed to operate through a rotary mechanism. Information on subunit interactions and topology and the function of individual residues in activity has begun to emerge from studies using site-directed mutagenesis and covalent modification.

  • The yeast V-ATPase requires a unique set of polypeptides for its assembly in the endoplasmic reticulum. Targeting of the V-ATPase seems to be controlled by signals that are located in the 100-kDa a subunit, although interaction with other cellular proteins, such as PDZ proteins, might be important.

  • Several mechanisms have been proposed to regulate V-ATPase activity, including reversible dissociation, disulphide-bond formation and changes in coupling efficiency. A new ubiquitin-ligase component has recently been shown to have a role in regulated assembly of the V-ATPase.

Abstract

The pH of intracellular compartments in eukaryotic cells is a carefully controlled parameter that affects many cellular processes, including intracellular membrane transport, prohormone processing and transport of neurotransmitters, as well as the entry of many viruses into cells. The transporters responsible for controlling this crucial parameter in many intracellular compartments are the vacuolar (H+)-ATPases (V-ATPases). Recent advances in our understanding of the structure and regulation of the V-ATPases, together with the mapping of human genetic defects to genes that encode V-ATPase subunits, have led to tremendous excitement in this field.

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Figure 1: Structural comparison of the V- and F-ATPases.
Figure 2: Function of V-ATPases in membrane transport.
Figure 3: Function of plasma membrane V-ATPases.
Figure 4: Electron microscopy of the V0 and V1V0 complexes.
Figure 5: Models of catalytic and noncatalytic nucleotide-binding sites on the V-ATPases.
Figure 6: Structure and function of the V0 domain.
Figure 7: Regulation of vacuolar acidification.

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Acknowledgements

The authors thank Y. Arata, S. Kawasaki-Nishi, E. Shao and J. Baleja of Tufts University and S. Wilkens of the University of California, Riverside for many helpful discussions. This work was supported by National Institutes of Health Grant as well as awards from the Medical Foundation and the Uehara Memorial Foundation.

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Authors and Affiliations

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

    Tsuyoshi Nishi & Michael Forgac

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  1. Tsuyoshi Nishi
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Correspondence to Michael Forgac.

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DATABASES

Interpro

V0 domain

 Saccharomyces Genome Database

Pma1

Rav1

Rav2

Skp1

STV1

VAM3

VMA4

Vma12

Vma21

Vma22

VPH1

Ynd1

 Swiss-Prot

ARF1

β1 integrin

β-COP

CD4

CLC-5

CLC-7

Rac1

Glossary

Na+/H+ EXCHANGER

This protein carries out antiport of Na+ and H+ across the plasma membrane and has an important role in regulation of cytoplasmic pH.

ENDOSOME

A vesicular compartment that is involved in the transport of internalized ligands from the plasma membrane to lysosomes, as well as in intracellular transport from Golgi to lysosomes.

LYSOSOME

An acidic compartment that contains digestive enzymes that are responsible for the degradation of various macromolecules.

SECRETORY VESICLE

A compartment that is used to sequester molecules within a cell and then deliver (secrete) them to the extracellular space by exocytosis.

RENAL INTERCALATED CELLS

Intercalated cells are present in the kidney cortex in the distal tubule and collecting duct. The A cells are involved in proton secretion and the B cells are involved in bicarbonate secretion.

OSTEOCLAST

A polarized and multinucleated cell that is responsible for bone resorption.

MACROPHAGE

A specialized cell that catches and destroys bacteria and other foreign cells.

MANNOSE 6-PHOSPHATE RECEPTOR

A receptor that ferries soluble lysosomal hydrolases to late endosomes by cycling between the trans-Golgi network (TGN) and late endosomes. It binds in the TGN to mannose 6-phosphate moieties on N-linked glycans of the hydrolases. It releases the hydrolases in late endosomes and returns to the TGN for another round of transport.

APICAL MEMBRANE

The plasma membrane of epithelial cells that faces the lumenal surface.

BASOLATERAL MEMBRANE

The plasma membrane of epithelial cells that faces adjacent cells and is in communication with the blood.

METABOLIC ACIDOSIS

A condition that is characterized by low plasma pH.

MECHANOSENSORY HAIR CELL

A cell in the inner ear that functions as a primary detector of sound.

NEUTROPHIL

The most common type of granulocyte cell that phagocytoses and destroys microorganisms.

EPIDIDYMIS

The coiled tube that overlies the testis where germ cells are stored and undergo further maturation.

VAS DEFERENS

Part of the duct system in testis that is responsible for the storage and maturation of sperm cells.

H+/K+ ANTIPORTER

A protein in the lumenal membrane of certain cells that lines the insect midgut, and which carries out exchange of H+ and K+ in opposite directions across this membrane.

PHAGOSOME

An organelle that is involved in the degradation of large particles, such as bacteria, that are taken up from the environment.

HEMICHANNEL

A half channel that reaches from one aqueous compartment to some point part way across the lipid bilayer.

ENERGY MINIMIZATION

The process of calculating the energy of different protein structures to deduce the most stable structure with the lowest energy.

COUPLING

The amount of proton transport that occurs relative to the amount of ATP hydrolysis. A 'tightly' coupled system is one in which proton transport occurs whenever ATP hydrolysis occurs, whereas in a completely 'uncoupled' system, ATP hydrolysis can occur without any accompanying proton transport.

RAS–cAMP PATHWAY

A signalling pathway that uses Ras and cAMP-activated protein kinase in response to various extracellular signals.

ACID LOAD

An excess of protons in the cytosol that can be the result of, for example, excess carbon dioxide delivery from the blood.

OSTEOPETROSIS

A genetic disesase in which insufficient bone resorption occurs, which leads to dense bones that, in some cases, lack marrow.

SCF UBIQUITIN-LIGASE COMPLEX

An E3 enzyme that catalyses the ubiquitylation of target proteins, using an F-Box protein as a specificity factor. SCF refers to 'Skp1/Cul1/F-Box protein'.

OSTEOPOROSIS

A disease in which bone resorption exceeds bone formation and results in weakened and brittle bones.

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Nishi, T., Forgac, M. The vacuolar (H+)-ATPases — nature's most versatile proton pumps. Nat Rev Mol Cell Biol 3, 94–103 (2002). https://doi.org/10.1038/nrm729

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