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

Bill, A and Popa, MO and van Diepen, MT and Gutierrez, A and Lilley, S and Velkova, M and Acheson, K and Choudhury, H and Renaud, NA and Auld, DS and Gosling, M and 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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