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