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

Author:

Varela Lorena1ORCID,Hendry Alex C.1,Cassar Joseph1,Martin-Escolano Ruben1,Cantoni Diego2,Ossa Felipe3,Edwards John C.4,Abdul-Salam Vahitha3,Ortega-Roldan Jose L.1ORCID

Affiliation:

1. School of Biosciences, University of Kent 1 , Canterbury CT2 7NJ , UK

2. Medway School of Pharmacy, The Universities of Kent and Greenwich at Medway 2 , Chatham ME7 4TB , UK

3. Centre for Cardiovascular Medicine and Device Innovation, William Harvey Research Institute (WHRI), Faculty of Medicine and Dentistry, Queen Mary University of London 3 , Room 213, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ , UK

4. St Louis University 4 Department of Internal Medicine , , 3635 Vista Ave., St Louis, MO 63110 , USA

Abstract

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.

Funder

Wellcome Trust

Alfonso Martin Escudero Foundation

Barts Charity

University of Kent

Publisher

The Company of Biologists

Subject

Cell Biology

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