Understanding structural basis of nephrogenic diabetes insipidus caused by mutations of aquaporin-2
Co-Applicant(s): Ana-Nicoleta Bondar, Leonid Brown
Lay Abstract
Water reabsorption in kidneys is a very important physiological process, and its deficiencies may lead to a number of diseases. One of them is called nephrogenic diabetes insipidus (NDI) which originates from insufficient activity of water-conducting membrane protein called aquaporin-2. Aquaporin-2 is normally found on the cellular surface (membrane) where it transports water across cell boundary. It was found that the main reason for the insufficient activity of aquaporin-2 in people suffering from NDI is its retention inside the cell, so that aquaporin-2 does not have a chance to perform its work of transporting water through the cellular surface. Some forms of NDI are caused by defects (mutations) in aquaporin-2, and the structural mechanism of retention of these defective variants of the protein is not known. The main goal of this proposal is to understand how mutation defects related to NDI affect structure of aquaporin-2 and its localization to cell membrane. We will use a novel technique of structural biology called Nuclear Magnetic Resonance, to study aquaporin-2 in cell membrane-like environment which ensures that this protein retains its native structure. Understanding the effect of mutations is important and may potentially pave the way to developing “aquaporin rescue” therapy for NDI, by which retained aquaporins can be rerouted to the cell surface and become functional.
