Structure and dynamics of an essential transmembrane segment of the proton translocation channel of V-ATPase

As life expectancy increases, the frequency of fractures originated by bone illnesses like osteoporosis is increasing throughout the world. According to theWorld HealthOrganization (WHO), between six and seven percent of people in the world are affectedby this disease (WHO, 2007). Approximately one in three women and one in seven men over the age of 50 years will at some stage suffer a bone fracture as a result of osteoporosis.

This particular disease is therefore regarded by the WHO as one of the world’s most important health problem. Osteoporosis leads to a decrease of the skeletal massto the point of structural bone instability and makes the patient susceptible to spontaneousbone fracture. As adult osteoporosis is always associated with enhanced boneresorption, advances in understanding and treating this type of diseases require the study of osteoclast biology. Osteoclasts, the bone-resorbing cells, and osteoclasts, the bone-forming cells, play the central role in the formation of the skeleton and regulation of its mass. A difference in activity of osteoclast and osteoblast bone cells can trigger theappearance of osteoporosis. During the bone-resorbing activity the extracellular protonconcentration is regulated via vacuolar proton V-ATPases (see Fig. 1.1).

The first evidences of the existence of V-ATPases in eukaryotic cells date from studies of (Kirshner et al., 1962; Njus et al., 1979; Mellman et al., 1986; Bashford et al., 1975). Inthese papers it was demonstrated that catecholamine uptake is driven by proton pumpinggenerated by an ATP-dependent proton pump, later named V-ATPase. Followingthese studies, V-ATPase was found to be present in the intracellular and plasma membranesof all eukaryotic cells, playing an important role in endocytosis, intracellulartargeting, protein processing and degradation (Finbow et al., 1997; Forgac et al., 1998;Nishi et al., 2002; Stevens et al., 1997; Forgac et al., 1999; Kane et al., 2006). When locatedin the plasma membranes the protein is involved in renal acidification, pH homeostasis, and bone resorption (Wieczorek et al., 1999).