Recent Insights into the Structure, Regulation, and Function of the V-ATPases

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2015-10, Vol.40 (10), p.611-622
• Main Authors: Cotter, Kristina, Stransky, Laura, McGuire, Christina, Forgac, Michael
• Format: Article
• Language: English
• Subjects: acidification; Animals; cancer; Cell Membrane - metabolism; cell signaling; Humans; membrane traffic; proton transport; Proton-Translocating ATPases - chemistry; Proton-Translocating ATPases - genetics; Proton-Translocating ATPases - metabolism; Structure-Activity Relationship; V-ATPase
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2015.08.005

The vacuolar (H+)-ATPases (V-ATPases) are ATP-dependent proton pumps that acidify intracellular compartments and are also present at the plasma membrane. They function in such processes as membrane traffic, protein degradation, virus and toxin entry, bone resorption, pH homeostasis, and tumor cell invasion. V-ATPases are large multisubunit complexes, composed of an ATP-hydrolytic domain (V1) and a proton translocation domain (V0), and operate by a rotary mechanism. This review focuses on recent insights into their structure and mechanism, the mechanisms that regulate V-ATPase activity (particularly regulated assembly and trafficking), and the role of V-ATPases in processes such as cell signaling and cancer. These developments have highlighted the potential of V-ATPases as a therapeutic target in a variety of human diseases. Recent structural studies of the V-ATPase have identified several novel features, including the presence of highly tilted α-helices in subunit a of the integral V0 domain that participate in proton translocation across the membrane. Regulated assembly of the V-ATPase from its peripheral V1 and integral V0 domains represents an important mechanism of controlling its activity in vivo and has been shown to be under control of various signaling pathways, including protein kinase A (PKA) and PI-3 kinase. The V-ATPase has been found to function in a variety of cellular signaling pathways, including the mechanistic target of rapamycin complex 1 (mTORC1), AMP-activated protein kinase (AMPK), Wnt, and Notch. The V-ATPase is emerging as important for cancer cell survival and invasion, making it a potential target in the development of anticancer drugs.