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Variomics screen identifies the reentrant loop of the calcium-activated chloride channel ANO1 that facilitates channel activation

Bill, A, Popa, MO, van Diepen, MT, Gutierrez, A, Lilley, S, Velkova, M, Acheson, K, Choudhury, H, Renaud, NA, Auld, DS, Gosling, M, Groot-Kormelink, PJ and Gaither, LA (2014) Variomics screen identifies the reentrant loop of the calcium-activated chloride channel ANO1 that facilitates channel activation. Journal of Biological Chemistry .

Abstract

The calcium-activated chloride channel ANO1 regulates multiple physiological processes. However, little is known about the mechanism of channel gating and regulation of ANO1 activity. Using a high-throughput, random mutagenesis based variomics screen, we generated and functionally characterized ~6000 ANO1 mutants and identified novel mutations that affected channel activity, intracellular trafficking or localization of ANO1. Mutations such as S741T increased ANO1 calcium-sensitivity and rendered ANO1 voltage independent, demonstrating a critical role of the reentrant loop in coupling calcium- and voltage-sensitivity of ANO1 and hence in regulating ANO1 activation. Our data presents the first, unbiased and comprehensive study of the structure-function relationship of ANO1. The novel ANO1 mutants reported have diverse functional characteristics, providing new tools to study ANO1 function in biological systems, paving the path for a better understanding of the function of ANO1 and its role in health and diseases

Item Type: Article
Additional Information: NIBR author: Bill, A institute: NIBR contributor address: NIBR, United States;NIBR, United States;NIBR, United States;NIBR, United States;NIBR, United States;NIBR, United States;NIBR, United States;NIBR, United States;NIBR, United States;NIBR, United States;NIBR, United States;NIBR, United States;Novartis Institutes for Biomedical Research, United States alex.gaither@novartis.com
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11
URI: https://oak.novartis.com/id/eprint/24949

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