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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 and Calloe, Kirstine , et al. (2019) In PLoS Biology 17(4).
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Biology
volume
17
issue
4
article number
e3000218
publisher
Public Library of Science (PLoS)
external identifiers
  • scopus:85065342646
  • pmid:31022181
ISSN
1545-7885
DOI
10.1371/journal.pbio.3000218
language
English
LU publication?
yes
id
9d129f04-b62c-4858-942f-a88cbcfeebcb
date added to LUP
2019-05-21 15:09:35
date last changed
2024-04-16 06:17:44
@article{9d129f04-b62c-4858-942f-a88cbcfeebcb,
  abstract     = {{<p>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.</p>}},
  author       = {{Wang, Kaituo and Preisler, Sarah Spruce and Zhang, Liying and Cui, Yanxiang and Missel, Julie Winkel and Grønberg, Christina and Gotfryd, Kamil and Lindahl, Erik and Andersson, Magnus and Calloe, Kirstine and Egea, Pascal F. and Klaerke, Dan Arne and Pusch, Michael and Pedersen, Per Amstrup and Zhou, Z. Hong and Gourdon, Pontus}},
  issn         = {{1545-7885}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{4}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS Biology}},
  title        = {{Structure of the human ClC-1 chloride channel}},
  url          = {{http://dx.doi.org/10.1371/journal.pbio.3000218}},
  doi          = {{10.1371/journal.pbio.3000218}},
  volume       = {{17}},
  year         = {{2019}},
}