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

View ORCID ProfileLorena Varela, View ORCID ProfileAlex C. Hendry, Joseph Cassar, Ruben Martin-Escolano, View ORCID ProfileDiego Cantoni, John C Edwards, Vahitha Abdul-Salam, View ORCID ProfileJose L. Ortega-Roldan
doi: https://doi.org/10.1101/2021.10.25.465729
Lorena Varela
1School of Biosciences. University of Kent. CT2 7NJ. Canterbury. UK
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  • ORCID record for Lorena Varela
Alex C. Hendry
1School of Biosciences. University of Kent. CT2 7NJ. Canterbury. UK
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Joseph Cassar
1School of Biosciences. University of Kent. CT2 7NJ. Canterbury. UK
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Ruben Martin-Escolano
1School of Biosciences. University of Kent. CT2 7NJ. Canterbury. UK
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Diego Cantoni
2Medway School of Pharmacy, The Universities of Kent and Greenwich at Medway, Chatham, ME7 4TB, UK
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John C Edwards
3Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA
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Vahitha Abdul-Salam
4Centre for Cardiovascular Medicine and Device Innovation, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Jose L. Ortega-Roldan
1School of Biosciences. University of Kent. CT2 7NJ. Canterbury. UK
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  • For correspondence: j.l.ortega-roldan@kent.ac.uk
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ABSTRACT

The 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 the plasma membranes, with membrane relocalisation linked to endothelial disfunction, tumour proliferation and metastasis. The molecular switch promoting CLIC1 activation remains unclear. Here, cellular chloride efflux assays and immunofluorescence microscopy studies have identified Zn2+ intracellular release as the trigger for CLIC1 activation and membrane relocalisation. Biophysical assays confirmed specific binding to Zn2+, inducing membrane association and enhancing chloride 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 activation of chloride efflux.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 26, 2021.
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Zn2+ triggered two-step mechanism of CLIC1 membrane insertion and activation into chloride channels
Lorena Varela, Alex C. Hendry, Joseph Cassar, Ruben Martin-Escolano, Diego Cantoni, John C Edwards, Vahitha Abdul-Salam, Jose L. Ortega-Roldan
bioRxiv 2021.10.25.465729; doi: https://doi.org/10.1101/2021.10.25.465729
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Zn2+ triggered two-step mechanism of CLIC1 membrane insertion and activation into chloride channels
Lorena Varela, Alex C. Hendry, Joseph Cassar, Ruben Martin-Escolano, Diego Cantoni, John C Edwards, Vahitha Abdul-Salam, Jose L. Ortega-Roldan
bioRxiv 2021.10.25.465729; doi: https://doi.org/10.1101/2021.10.25.465729

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