Structure of the human ClC-1 chloride channel

Research output: Contribution to journalArticle


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.


  • 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
External organisations
  • University of Copenhagen
  • University of California, Los Angeles
  • Stockholm University
  • Umeå University
  • Institute of Biophysics (IBF), CNR
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
Original languageEnglish
Article numbere3000218
JournalPLoS Biology
Issue number4
Publication statusPublished - 2019 Apr 25
Publication categoryResearch