Structure, function and regulation of the vacuolar (H+)‐ATPases

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Abstract
The vacuolar (H+)‐ATPases (or V‐ATPases) function to acidify intracellular compartments in eukaryotic cells, playing an important role in such processes as receptor‐mediated endocytosis, intracellular membrane traffic, protein degradation and coupled transport. V‐ATPases in the plasma membrane of specialized cells also function in renal acidification, bone resorption and cytosolic pH maintenance. The V‐ATPases are composed of two domains. The V1 domain is a 570‐kDa peripheral complex composed of 8 subunits (subunits A–H) of molecular weight 70–13 kDa which is responsible for ATP hydrolysis. The V0 domain is a 260‐kDa integral complex composed of 5 subunits (subunits a–d) which is responsible for proton translocation. The V‐ATPases are structurally related to the F‐ATPases which function in ATP synthesis. Biochemical and mutational studies have begun to reveal the function of individual subunits and residues in V‐ATPase activity. A central question in this field is the mechanism of regulation of vacuolar acidification in vivo. Evidence has been obtained suggesting a number of possible mechanisms of regulating V‐ATPase activity, including reversible dissociation of V1 and V0 domains, disulfide bond formation at the catalytic site and differential targeting of V‐ATPases. Control of anion conductance may also function to regulate vacuolar pH. Because of the diversity of functions of V‐ATPases, cells most likely employ multiple mechanisms for controlling their activity.