Structure of the human ClC-1 chloride channel
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Structure of the human ClC-1 chloride channel. / 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.
I: PLOS Biology, Bind 17, Nr. 4, e3000218, 2019, s. 1-20.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Structure of the human ClC-1 chloride channel
AU - Wang, Kaituo
AU - Preisler, Sarah Spruce
AU - Zhang, Liying
AU - Cui, Yanxiang
AU - Missel, Julie Winkel
AU - Grønberg, Christina
AU - Gotfryd, Kamil
AU - Lindahl, Erik
AU - Andersson, Magnus
AU - Calloe, Kirstine
AU - Egea, Pascal F
AU - Klaerke, Dan Arne
AU - Pusch, Michael
AU - Pedersen, Per Amstrup
AU - Zhou, Z. Hong
AU - Gourdon, Pontus
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pbio.3000218
DO - 10.1371/journal.pbio.3000218
M3 - Journal article
C2 - 31022181
VL - 17
SP - 1
EP - 20
JO - PLoS Biology
JF - PLoS Biology
SN - 1544-9173
IS - 4
M1 - e3000218
ER -
ID: 217156477