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PDBsum entry 6qv6
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Membrane protein
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PDB id
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6qv6
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References listed in PDB file
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Key reference
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Title
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Structure of the human clc-1 chloride channel.
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Authors
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K.Wang,
S.S.Preisler,
L.Zhang,
Y.Cui,
J.W.Missel,
C.Grønberg,
K.Gotfryd,
E.Lindahl,
M.Andersson,
K.Calloe,
P.F.Egea,
D.A.Klaerke,
M.Pusch,
P.A.Pedersen,
Z.H.Zhou,
P.Gourdon.
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Ref.
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PLoS Biol, 2019,
17,
e3000218.
[DOI no: ]
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PubMed id
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Abstract
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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.
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