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

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posted on 2023-06-08, 19:46 authored by Anke Bill, M Oana Popa, Michiel T Van Diepen, Abraham Gutierrez, Sarah Lilley, Maria Velkova, Kathryn Acheson, Hedaythul Choudhury, Nicole A Renaud, Douglas S Auld, Martin Gosling, Paul J Groot-Kormelink, L Alex Gaither
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.

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Publication status

  • Published

File Version

  • Published version

Journal

Journal of Biological Chemistry

ISSN

0021-9258

Publisher

American Society for Biochemistry and Molecular Biology

Issue

2

Volume

290

Page range

889-903

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2015-01-27

First Open Access (FOA) Date

2021-03-09

First Compliant Deposit (FCD) Date

2021-03-09

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