title: Eukaryotic V-ATPase: novel structural findings and functional insights.
abstract: The eukaryotic V-type adenosine triphosphatase (V-ATPase) is a multi-subunit membrane protein complex that is evolutionarily related to F-type adenosine triphosphate (ATP) synthases and A-ATP synthases. These ATPases/ATP synthases are functionally conserved and operate as rotary proton-pumping nano-motors, invented by Nature billions of years ago. In the first part of this review we will focus on recent structural findings of eukaryotic V-ATPases and discuss the role of different subunits in the function of the V-ATPase holocomplex. Despite structural and functional similarities between rotary ATPases, the eukaryotic V-ATPases are the most complex enzymes that have acquired some unconventional cellular functions during evolution. In particular, the novel roles of V-ATPases in the regulation of cellular receptors and their trafficking via endocytotic and exocytotic pathways were recently uncovered. In the second part of this review we will discuss these unique roles of V-ATPases in modulation of function of cellular receptors, involved in the development and progression of diseases such as cancer and diabetes as well as neurodegenerative and kidney disorders. Moreover, it was recently revealed that the V-ATPase itself functions as an evolutionarily conserved pH sensor and receptor for cytohesin-2/Arf-family GTP-binding proteins. Thus, in the third part of the review we will evaluate the structural basis for and functional insights into this novel concept, followed by the analysis of the potentially essential role of V-ATPase in the regulation of this signaling pathway in health and disease. Finally, future prospects for structural and functional studies of the eukaryotic V-ATPase will be discussed.
authors: Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Simches Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Kadmon Pharmaceuticals Corporation, Alexandria Center for Life Science, 450 East 29th Street, New York, NY 10016, USA. Electronic address: Vladimir_Marshansky@hms.harvard.edu.
authors: Vladimir
authors: V
authors: Marshansky
authors: Molecular Structure and Function Program, The Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON M5G 1X8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5G 1X8, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors: John L
authors: JL
authors: Rubinstein
authors: Nanyang Technological University, Division of Structural Biology and Biochemistry, School of Biological Sciences, Singapore 637551, Republic of Singapore; Bioinformatics Institute, A(⁎)STAR, 60 Nanyang Drive, Singapore 637551, Republic of Singapore.
authors: Gerhard
authors: G
authors: Grüber
mesh_terms: D008958:Models, Molecular; D036103:Nanotechnology; D011487:Protein Conformation; D025262:Vacuolar Proton-Translocating ATPases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D025262:Vacuolar Proton-Translocating ATPases
keywords: Cytohesin-2/Arf's signaling; Eukaryotic V-ATPase; Regulation of cellular receptors function; Rotary proton-pumping nano-motor; Trafficking via endocytotic and exocytotic pathways; pH sensor