Gaitán-Peñas, Héctor;
Perez-Gonzalez, Anna Priscil·la;
González-Subías, Marc;
Zdebik, Anselm A;
Gasull, Xavier;
Buey, Rubén M;
Errasti-Murugarren, Ekaitz;
(2025)
Identification of a crosstalk between ClC-1 C-terminal CBS domains and the transmembrane region.
The Journal of Physiology
10.1113/JP287718.
(In press).
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18229_3_merged_1737545202.pdf - Accepted Version Access restricted to UCL open access staff until 8 February 2026. Download (1MB) |
Abstract
CLC channels and transporters have large C-terminal regions which contain two cystathionine β-synthetase (CBS) domains. It has been hypothesized that conformational changes in these domains upon nucleotide binding modulate the gating of the CLC dimer. It is not clear how rearrangements that occur in the CBS domains are transmitted to the ion pathway, as CBS domains interact with the rest of the channel at multiple locations and some of these sites are not visible in recent solved cryogenic electron microscopy structures or are difficult to model using the AlphaFold server. Using ClC-1 as a model, we started working with a described ClC-1 mutation (H835R) located in the first alpha helix of the CBS2 domain which changes the voltage dependence of gating. We then identified several residues located in the disorganized loop after helix R (R-linker) that revert the phenotype of this mutation. We additionally proved that R-linker's function is connected to the CBS2 domain as current intensity, plasma membrane levels and gating defects of several R-linker variants were corrected by adding the mutation H835R. Furthermore, cross-linking studies using newly developed split-cysless ClC-1 channels containing specific cysteine mutants in the R-linker and the CBS2 domain indicate that these two regions are in close contact. Considering these new results, we propose that conformational changes occurring in the CBS domains could be transmitted to the CLC intracellular chloride binding site by means of its interaction with the R-linker.
| Type: | Article |
|---|---|
| Title: | Identification of a crosstalk between ClC-1 C-terminal CBS domains and the transmembrane region |
| Location: | England |
| DOI: | 10.1113/JP287718 |
| Publisher version: | https://doi.org/10.1113/jp287718 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | ClC proteins; CBS domains; gating; intramolecular protein interaction |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10205267 |
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