Cryo-EM structures of the human volume-regulated anion channel LRRC8
Cryo-EM structures of the human volume-regulated anion channel LRRC8
复制标题
人体容量调节阴离子通道 LRRC8 的冷冻电镜结构
DOI：
10.1038/s41594-018-0109-6
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发表时间：
2018-09-01
影响因子：
16.8
通讯作者：
Nureki, Osamu
中科院分区：
文献类型：
--
作者：
Kasuya, Go;Nakane, Takanori;Nureki, Osamu
在渗透压变化的情况下维持细胞体积对于细胞正常功能至关重要。富含亮氨酸重复序列8蛋白是阴离子选择性通道，在细胞肿胀时排出阴离子以减小细胞体积。在此，我们展示了通过单颗粒冷冻电镜确定的人富含亮氨酸重复序列8A的结构。该结构呈现出六聚体组装形式，跨膜区域具有类似于间隙连接通道的拓扑结构。具有15个富含亮氨酸重复序列的LRR区域形成一个长而扭曲的弧形。通道孔位于中心轴上，在细胞外一侧收缩，细胞外螺旋顶端高度保守的极性和带电残基有助于阴离子和其他渗透物的通透性。确定了两种结构群体，分别对应紧密和松弛构象。对这两种构象进行比较表明，LRR区域具有灵活性和可移动性，存在刚体运动，这可能与通道开放时的结构转变有关。
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.