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

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.