Structure and Roles of V-type ATPases

Structures of the intact yeast V-ATPase have revealed the rotary mechanism of the complex and the dynamics associated with enzyme activity. The structures of the isolated V1 and VO regions have shown conformational changes associated with reversible disassembly and silencing of activity. An atomic model of the VO region has revealed the proton-translocation pathway. Biochemical studies have shown the isoform-specific characteristics of yeast V-ATPase and the influence of different lipids on targeting and activity. V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps. V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes. Enzymatic activity can be modulated by regulated and reversible disassembly of the complex, and several subunits of mammalian V-ATPase have multiple isoforms that are differentially localized. Although the biochemical properties of the different isoforms are currently unknown, mutations in specific subunit isoforms have been associated with various diseases, making V-ATPases potential drug targets. V-ATPase structure and activity have been best characterized in Saccharomyces cerevisiae, where recent structures have revealed details about the dynamics of the enzyme, the proton translocation pathway, and conformational changes associated with regulated disassembly and autoinhibition. V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps. V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes. Enzymatic activity can be modulated by regulated and reversible disassembly of the complex, and several subunits of mammalian V-ATPase have multiple isoforms that are differentially localized. Although the biochemical properties of the different isoforms are currently unknown, mutations in specific subunit isoforms have been associated with various diseases, making V-ATPases potential drug targets. V-ATPase structure and activity have been best characterized in Saccharomyces cerevisiae, where recent structures have revealed details about the dynamics of the enzyme, the proton translocation pathway, and conformational changes associated with regulated disassembly and autoinhibition. a bone disease caused by defects in osteoclast activity and bone resorption, resulting in abnormally dense bones that are more prone to fracture. a connective tissue disorder characterized by loose and inelastic skin and by abnormalities in other connective tissues including the blood vessels and joints as a result of impaired elastin formation. a condition resulting from impaired acid secretion into the urine from the distal tubule of the kidney, resulting in systemic acidosis. related protein variants that can arise from a single gene as a result of splicing variations, or from separate genes. Protein isoforms tend to have a similar structure and function but may differ in activity level, regulation, or expression pattern. a family of multisubunit membrane protein complexes that couple proton transport across a membrane to the synthesis or hydrolysis of ATP through a rotary catalytic mechanism. This family includes the F-type ATP synthase, vacuolar-type ATPase (V-ATPase), and the archaeal V/A-ATPase. Rotary ATPases have a conserved overall structure characterized by a soluble catalytic region that carries out ATP synthesis or hydrolysis and a membrane-embedded region that is responsible for proton translocation. a phenotype observed in yeast lacking functional V-ATPase. Defects in vacuolar acidification lead to several different characteristics in yeast, including an inability to grow at pH 7 or higher, sensitivity to elevated extracellular levels of calcium and heavy metals, and an inability to grow on medium with typical levels non-fermentable carbon sources. The phenotype has been useful for identifying V-ATPase subunits and assembly factors, as well as residues that are important for V-ATPase function.