Structure of the human ClC-1 chloride channel

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Dokumenter

Kaituo Wang, Sarah Spruce Preisler, Liying Zhang, Yanxiang Cui, Julie Winkel Missel, Christina Grønberg, Kamil Gotfryd, Erik Lindahl, Magnus Andersson, Kirstine Calloe, Pascal F Egea, Dan Arne Klaerke, Michael Pusch, Per Amstrup Pedersen, Z. Hong Zhou, Pontus Gourdon

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-β-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.

OriginalsprogEngelsk
Artikelnummere3000218
TidsskriftPLOS Biology
Vol/bind17
Udgave nummer4
Sider (fra-til)1-20
ISSN1544-9173
DOI
StatusUdgivet - 2019

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