The subunit of the vacuolar proton pump is a V-ATPase that has two different isoforms. The type I isoform contains an 18-base pair insert and is expressed in brain, whereas the truncated type II isoform is more widely expressed, including lung, kidney and spleen. The subunit of the vacuolar proton pump is located in clathrin-coated vesicles and is also found in osteoclasts. It consists of two fundamental domains, a hydrophilic amino-terminus, which has greater than 30% charged residues, and a hydrophobic carboxy terminus, which contains at least six transmembrane regions. The proton pump functions in coupling ATP hydrolysis by the cytoplasmic subunits to proton translocation by the intramembranous components of the pump. The inactivation of the osteoclast-specific vacuolar proton ATPase subunit is responsible for the lack of the enzyme in the apical membranes of osteoclast cells in osteosclerotic mutant mice, thus preventing the resorption function of these cells and leading to the osteopetrotic phenotype. The subunit, which co-localizes with the late endosomal marker Rab7 on vacuolar membranes, is essential for vacuole formation by selective swelling of late endosomes.