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

ヒト由来LRRC8の全体構造をクライオ電子顕微鏡を用いた単粒子解析法によって解析
今回の構造解析によりロイシンリッチ・リピート配列を帯びた（LRRC8）アニオンチャネルの分子メカニズムが解明され、今後さらに理解が深まる事が期待される

Abstract

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.

分解能

最高分解能3.8 Å（平均4.25Å）

Citation

Kasuya, T. Nakane, T. Yokoyama, Y. Jia, M. Inoue, K. Watanabe, R. Nakamura, T. Nishizawa, T. Kusakizako, A. Tsutsumi, H. Yanagisawa, N. Dohmae, M. Hattori, H. Ichijo, Z. Yan, M. Kikkawa, M. Shirouzu, R. Ishitani, O. Nureki Nat. Struct. Mol. Biol. 25, 797-804 (2018).