Eukaryotic V-ATPase and Its Super-complexes: From Structure and Function to Disease and Drug Targeting

The eukaryotic vacuolar-type ATPase (V-ATPase) is a multi-subunit membrane protein complex, which is evolutionarily conserved from yeast to human. It is also functionally conserved and operates as a rotary proton pumping nano-motor. In the first part of this chapter we discuss the structure and function of the yeast V-ATPase (V₁V_O) holoenzyme, We focus on the structural features of its subunits forming both catalytic V₁ and proton conducting V_O sectors. Particularly, the recently solved structure of DF-subunit complex is discussed in relation to the energy coupling and regulation of yeast V-ATPase. It is noteworthy that the structure could contribute to understanding the function and regulation of V-ATPases of eukaryotes including human, leading to the rational design of specific inhibitors for medical applications. In addition to the well characterized role as proton pump, V-ATPases have acquired alternative cellular functions during evolution. In the second part we analyze novel roles of V-ATPase in function, signaling, and vesicular trafficking of cellular receptors. Our recent studies have uncovered that V-ATPase itself functions as an evolutionarily conserved pH-sensing and signaling receptor, which forms super-complex with aldolase/cytohesin-2/Arf1,6 small GTPases in early endosomes. On the other hand, V-ATPase forms a super-complex with mTORC1/Ragulator/Rag/Rheb small GTPases in late endosome/lysosomes and is involved in amino-acids sensing and monitoring nutritional state of cells. Finally, we discuss the role of V-ATPase in the development and progression of various diseases including cancer, diabetes, and osteopetrosis among others. We also present emerging approaches and future perspectives for specific drug targeting to V-ATPase and its super-complexes.