Ministry of Education, Culture, Sports, Science and Technology (Japan)
16H06294
Japan
Japan Society for the Promotion of Science (JSPS)
19K23833
Japan
Citation
Journal: Commun Biol / Year: 2020 Title: Cryo-EM structure of the volume-regulated anion channel LRRC8D isoform identifies features important for substrate permeation. Authors: Ryoki Nakamura / Tomohiro Numata / Go Kasuya / Takeshi Yokoyama / Tomohiro Nishizawa / Tsukasa Kusakizako / Takafumi Kato / Tatsuya Hagino / Naoshi Dohmae / Masato Inoue / Kengo Watanabe / ...Authors: Ryoki Nakamura / Tomohiro Numata / Go Kasuya / Takeshi Yokoyama / Tomohiro Nishizawa / Tsukasa Kusakizako / Takafumi Kato / Tatsuya Hagino / Naoshi Dohmae / Masato Inoue / Kengo Watanabe / Hidenori Ichijo / Masahide Kikkawa / Mikako Shirouzu / Thomas J Jentsch / Ryuichiro Ishitani / Yasunobu Okada / Osamu Nureki / Abstract: Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of the five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC). LRRC8A and at ...Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of the five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC). LRRC8A and at least one of the other LRRC8 isoforms assemble into heteromers to generate VRAC transport activities. Despite the availability of the LRRC8A structures, the structural basis of how LRRC8 isoforms other than LRRC8A contribute to the functional diversity of VRAC has remained elusive. Here, we present the structure of the human LRRC8D isoform, which enables the permeation of organic substrates through VRAC. The LRRC8D homo-hexamer structure displays a two-fold symmetric arrangement, and together with a structure-based electrophysiological analysis, revealed two key features. The pore constriction on the extracellular side is wider than that in the LRRC8A structures, which may explain the increased permeability of organic substrates. Furthermore, an N-terminal helix protrudes into the pore from the intracellular side and may be critical for gating.
History
Deposition
Feb 20, 2020
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Header (metadata) release
Jun 17, 2020
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Map release
Jun 17, 2020
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Update
Jun 17, 2020
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Current status
Jun 17, 2020
Processing site: PDBj / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
EMPIAR-10383 (Title: CryoEM structure of human LRRC8D / Data size: 1.7 TB Data #1: Unaligned movies of human LRRC8D isoform [micrographs - multiframe])
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: Blotted for 4 seconds before plunging..
Details
This sample was monodisperse
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Electron microscopy
Microscope
FEI TALOS ARCTICA
Temperature
Min: 79.55 K / Max: 79.55 K
Details
Specimen holder is FEI Talos Arctica autogrid holder.
Image recording
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-40 / Number real images: 3397 / Average exposure time: 15.0 sec. / Average electron dose: 50.0 e/Å2
Electron beam
Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
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