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Structure of the human ClC-1 chloride channel
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Number of Authors: 162019 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 17, no 4, article id e3000218Article in journal (Refereed) Published
Abstract [en]

ClC-1 protein channels facilitate rapid passage of chloride ions across cellular membranes, thereby orchestrating skeletal muscle excitability. Malfunction of ClC-1 is associated with myotonia congenita, a disease impairing muscle relaxation. Here, we present the cryo-electron microscopy (cryo-EM) structure of human ClC-1, uncovering an architecture reminiscent of that of bovine ClC-K and CLC transporters. The chloride conducting pathway exhibits distinct features, including a central glutamate residue (fast gate) known to confer voltage-dependence (a mechanistic feature not present in ClC-K), linked to a somewhat rearranged central tyrosine and a narrower aperture of the pore toward the extracellular vestibule. These characteristics agree with the lower chloride flux of ClC-1 compared with ClC-K and enable us to propose a model for chloride passage in voltage-dependent CLC channels. Comparison of structures derived from protein studied in different experimental conditions supports the notion that pH and adenine nucleotides regulate ClC-1 through interactions between the so-called cystathionine-beta-synthase (CBS) domains and the intracellular vestibule (slow gating). The structure also provides a framework for analysis of mutations causing myotonia congenita and reveals a striking correlation between mutated residues and the phenotypic effect on voltage gating, opening avenues for rational design of therapies against ClC-1-related diseases.

Place, publisher, year, edition, pages
2019. Vol. 17, no 4, article id e3000218
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:su:diva-169067DOI: 10.1371/journal.pbio.3000218ISI: 000466600400031PubMedID: 31022181OAI: oai:DiVA.org:su-169067DiVA, id: diva2:1318273
Available from: 2019-05-27 Created: 2019-05-27 Last updated: 2019-05-27Bibliographically approved

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Lindahl, ErikEgea, Pascal F.
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