PT  - JOURNAL ARTICLE
AU  - Go Kasuya
AU  - Takanori Nakane
AU  - Takeshi Yokoyama
AU  - Yanyan Jia
AU  - Masato Inoue
AU  - Kengo Watanabe
AU  - Ryoki Nakamura
AU  - Tomohiro Nishizawa
AU  - Tsukasa Kusakizako
AU  - Akihisa Tsutsumi
AU  - Haruaki Yanagisawa
AU  - Naoshi Dohmae
AU  - Motoyuki Hattori
AU  - Hidenori Ichijo
AU  - Zhiqiang Yan
AU  - Masahide Kikkawa
AU  - Mikako Shirouzu
AU  - Ryuichiro Ishitani
AU  - Osamu Nureki
TI  - Cryo-EM structure of the volume-regulated anion channel LRRC8
AID  - 10.1101/331207
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 331207
4099  - http://biorxiv.org/content/early/2018/05/25/331207.short
4100  - http://biorxiv.org/content/early/2018/05/25/331207.full
AB  - Maintenance of cell volume against osmotic change is crucial for proper cell functions, such as cell proliferation and migration. The leucine-rich repeat-containing 8 (LRRC8) proteins are anion selective channels, and were recently identified as pore components of the volume-regulated anion channels (VRACs), which extrude anions to decrease the cell volume upon cell-swelling. Here, we present the human LRRC8A structure, determined by a single-particle cryo-electron microscopy analysis. The sea anemone-like structure represents a trimer of dimers assembly, rather than a symmetrical hexameric assembly. The four-spanning transmembrane region has a gap junction channel-like membrane topology, while the LRR region containing 15 leucine-rich repeats forms a long twisted arc. The channel pore is along the central axis and constricted on the extracellular side, where the highly conserved polar and charged residues at the tip of the extracellular helix contribute to the anion and other osmolyte permeability. Comparing the two structural populations facilitated the identification of both compact and relaxed conformations, suggesting that the LRR region is flexible and mobile with rigid-body motions, which might be implicated in structural transitions upon pore opening. Overall, our structure provides a framework for understanding the molecular mechanisms of this unique class of ion channels.