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Nat Struct Mol Biol. 2018 Sep;25(9):797-804. doi: 10.1038/s41594-018-0109-6. Epub 2018 Aug 20.

Cryo-EM structures of the human volume-regulated anion channel LRRC8.

Author information

1
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
2
Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
3
MRC Laboratory of Molecular Biology, Cambridge, UK.
4
Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama-shi, Kanagawa, Japan.
5
State Key Laboratory of Medical Neurobiology, Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Yangpu District, Shanghai, China.
6
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
7
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
8
RIKEN, Global Research Cluster, Wako-shi, Saitama, Japan.
9
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Yangpu District, Shanghai, China.
10
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. ishitani@bs.s.u-tokyo.ac.jp.
11
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. nureki@bs.s.u-tokyo.ac.jp.

Abstract

Maintenance of cell volume against osmotic change is crucial for proper cell functions. Leucine-rich repeat-containing 8 proteins are anion-selective channels that extrude anions to decrease the cell volume on cellular swelling. Here, we present the structure of human leucine-rich repeat-containing 8A, determined by single-particle cryo-electron microscopy. The structure shows a hexameric assembly, and the transmembrane region features a topology similar to gap junction channels. The LRR region, with 15 leucine-rich repeats, forms a long, twisted arc. The channel pore is located along the central axis and constricted on the extracellular side, where highly conserved polar and charged residues at the tip of the extracellular helix contribute to permeability to anions and other osmolytes. Two structural populations were identified, corresponding to compact and relaxed conformations. Comparing the two conformations suggests that the LRR region is flexible and mobile, with rigid-body motions, which might be implicated in structural transitions on pore opening.

PMID:
30127360
DOI:
10.1038/s41594-018-0109-6
[Indexed for MEDLINE]

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