A Zn2+-triggered two-step mechanism of CLIC1 membrane insertion and activation into chloride channels

Varela, L., Hendry, A. C., Cassar, J., Martin-Escolano, R., Cantoni, D. , Ossa, F., Edwards, J. C., Abdul-Salam, V. and Ortega-Roldan, J. L. (2022) A Zn2+-triggered two-step mechanism of CLIC1 membrane insertion and activation into chloride channels. Journal of Cell Science, 135(15), jcs259704. (doi: 10.1242/jcs.259704) (PMID:35833483) (PMCID:PMC9511705)

Abstract

The chloride intracellular channel (CLIC) protein family displays the unique feature of altering its structure from a soluble form to a membrane-bound chloride channel. CLIC1, a member of this family, is found in the cytoplasm or in internal and plasma membranes, with membrane relocalisation linked to endothelial disfunction, tumour proliferation and metastasis. The molecular switch promoting CLIC1 activation remains under investigation. Here, cellular Cl− efflux assays and immunofluorescence microscopy studies have identified intracellular Zn2+ release as the trigger for CLIC1 activation and membrane insertion. Biophysical assays confirmed specific binding to Zn2+, inducing membrane association and enhancing Cl− efflux in a pH-dependent manner. Together, our results identify a two-step mechanism with Zn2+ binding as the molecular switch promoting CLIC1 membrane insertion, followed by pH-mediated activation of Cl− efflux.

• Item Type: Articles
• Additional Information: We acknowledge support from the Wellcome Trust Seed Award (207743/Z/17/Z). R.M.-E. is supported by a fellowship from the Alfonso Martin Escudero Foundation. V.A.-S. is supported by Barts Charity’s Rising Star programme. Open Access funding provided by University of Kent.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cantoni, Dr Diego

Creator Roles

Cantoni, D.: Methodology, Visualization

• Authors: Varela, L., Hendry, A. C., Cassar, J., Martin-Escolano, R., Cantoni, D., Ossa, F., Edwards, J. C., Abdul-Salam, V., and Ortega-Roldan, J. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Cell Science
• Publisher: Company of Biologists
• ISSN: 0021-9533
• ISSN (Online): 1477-9137
• Copyright Holders: Copyright: © 2022. Published by The Company of Biologists Ltd
• First Published: First published in Journal of Cell Science 135(15): jcs259704
• Publisher Policy: Reproduced under a Creative Commons licence