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

Bill, Anke, Popa, M Oana, Van Diepen, Michiel T, Gutierrez, Abraham, Lilley, Sarah, Velkova, Maria, Acheson, Kathryn, Choudhury, Hedaythul, Renaud, Nicole A, Auld, Douglas S, Gosling, Martin, Groot-Kormelink, Paul J and Gaither, L Alex (2015) Variomics screen identifies the re-entrant loop of the calcium-activated chloride channel ANO1 that facilitates channel activation. Journal of Biological Chemistry, 290 (2). pp. 889-903. ISSN 0021-9258

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Abstract

The calcium-activated chloride channelANO1regulates 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 calcium gating voltage-independent, demonstrating a critical role of the re-entrant loop in coupling calcium and voltage sensitivity of ANO1 and hence in regulating ANO1 activation. Our data present 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
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry
Depositing User: Tom Gittoes
Date Deposited: 27 Jan 2015 11:52
Last Modified: 27 Jan 2015 11:52
URI: http://sro.sussex.ac.uk/id/eprint/52450
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