Eukaryotic V-ATPase: Novel structural findings and functional insights

Eukaryotic V-ATPase: Novel structural findings and functional insights
Eukaryotic V-ATPase: Novel structural findings and functional insights
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Biochimica et Biophysica Acta (BBA) - Bioenergetics
Publication Date:
04 February 2014
Vladimir Marshansky, John L. Rubinstein, Gerhard Grüber, Eukaryotic V-ATPase: Novel structural findings and functional insights, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Volume 1837, Issue 6, 2014, Pages 857-879, ISSN 0005-2728,
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.
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Funding Info:
Original work in the authors' laboratories is supported by NIH DK038452, BADERC DK057521-08 (Marshansky) as well as by A*STAR BMRC, 09/1/22/19/609, Ministry of Education Tier 2 (MOE2011-T2-2-156; ARC 18/12), Singapore (Grüber) and by CIHR MOP81294 (Rubinstein).
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