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Structure of the hu...
Structure of the human ClC-1 chloride channel
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- Wang, Kaituo (author)
- University of California, Los Angeles,University of Copenhagen
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- Preisler, Sarah Spruce (author)
- University of Copenhagen
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- Zhang, Liying (author)
- University of Copenhagen
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- Cui, Yanxiang (author)
- University of California, Los Angeles
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- Missel, Julie Winkel (author)
- University of Copenhagen
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- Gronberg, Christina (author)
- University of Copenhagen
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- Gotfryd, Kamil (author)
- University of Copenhagen
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- Lindahl, Erik (author)
- Stockholm University,Stockholms universitet,Institutionen för biokemi och biofysik
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- Andersson, Magnus (author)
- Umeå University,Umeå universitet,Kemiska institutionen
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- Calloe, Kirstine (author)
- University of Copenhagen
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- Egea, Pascal F. (author)
- University of California, Los Angeles
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- Klaerke, Dan Arne (author)
- University of Copenhagen
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- Pusch, Michael (author)
- CNR Institute of Biophysics (IBF)
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- Pedersen, Per Amstrup (author)
- University of Copenhagen
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- Zhou, Z. Hong (author)
- University of California, Los Angeles
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- Gourdon, Pontus (author)
- Lund University,Lunds universitet,Membranproteinstrukturbiologi,Forskargrupper vid Lunds universitet,Membrane Protein Structural Biology,Lund University Research Groups,University of Copenhagen
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(creator_code:org_t)
- 2019-04-25
- 2019
- English.
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In: PLoS biology. - : Public Library Science. - 1544-9173 .- 1545-7885. ; 17:4
- Related links:
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https://umu.diva-por... (primary) (Raw object)
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https://doi.org/10.1...
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http://dx.doi.org/10... (free)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Wang, Kaituo
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Preisler, Sarah ...
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Zhang, Liying
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Cui, Yanxiang
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Missel, Julie Wi ...
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Gronberg, Christ ...
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show more...
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Gotfryd, Kamil
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Lindahl, Erik
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Andersson, Magnu ...
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Calloe, Kirstine
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Egea, Pascal F.
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Klaerke, Dan Arn ...
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Pusch, Michael
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Pedersen, Per Am ...
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Zhou, Z. Hong
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Gourdon, Pontus
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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PLoS biology
- By the university
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Umeå University
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Stockholm University
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Lund University