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Overview

The V-ATPase is an acid pumping protein that controls pH at sub-cellular, cellular, local and systemic levels. It is implicated in rare (e.g. renal distal tubular acidosis, osteopetrosis), as well as more common diseases, such as various types of cancer, osteoporosis, Alzheimer's and Parkinson's neurodegenerative diseases. This enzyme is, therefore, an emerging drug target for treatment of all these diseases. However, the mechanisms that are involved in V-ATPase regulation in both physiological and pathophysiological conditions are poorly understood. To address this question, we performed the first systematic proteome-wide analysis of V-ATPase protein-protein interactions (1). Some previously known as well as several novel V-ATPase interacting proteins were revealed; five of these proteins, called DMXL1, DMXL2, WDR7, NCOA7 and OXR1 were found to regulate V-ATPase activity in mammalian cells. We use a combination of biochemical, molecular biology, structural and bioinformatics methods to study the molecular mechanisms of this regulation, as well as mouse knockout models to study the potential role of these and other V-ATPase interacting proteins in kidney function and acid-base homeostasis. This work is currently supported by Dr. Dennis Brown, director of the Program in Membrane Biology (PMB), affiliated with the MGH interdisciplinary Center for Systems Biology (CSB).

References

  1. Merkulova M, Păunescu TG, Azroyan A, Marshansky V, Breton S, Brown D. Mapping the H(+) (V)-ATPase interactome: identification of proteins involved in trafficking, folding, assembly and phosphorylation.Sci. Rep. 2015; 5: 14827.
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