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Structure of the human ClC-1 chloride channel.

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

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.

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