Structure of the human ClC-1 chloride channel

• DOI: 10.1371/journal.pbio.3000218
• Publication Date: 2019-04-25T17:26:32Z
• Authors: Kaituo Wang; Sarah Spruce Prei...; 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
• Keywords: Chloride channel; Myotonia congenita

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