Structure of a volume-regulated anion channel of the LRRC8 family
Structure of a volume-regulated anion channel of the LRRC8 family
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DOI：
10.1038/s41586-018-0134-y
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发表时间：
2018-06-14
期刊：
影响因子：
64.8
通讯作者：
Dutzler, Raimund
中科院分区：
文献类型：
--
作者：
Deneka, Dawid;Sawicka, Marta;Dutzler, Raimund
容量调节阴离子通道响应于低渗应激而被激活。这些通道由富含亮氨酸重复序列的蛋白质8（LRRC8）家族的密切相关的旁系同源物组成，所述旁系同源物共组装以形成六聚体复合物。在这里，使用冷冻电子显微镜和X射线晶体学，我们确定了一个同聚体通道的强制性亚基LRRC8A的结构。该蛋白传导离子，并具有与内源性异聚体通道相同的特性。它的模块化结构由一个跨膜孔结构域，随后是一个胞质亮氨酸重复结构域组成。结构上与连接蛋白蛋白相关的跨膜结构域在细胞质中较宽，但在外部被作为选择性过滤器的结构单元限制。过量的碱性残留物在过滤器和整个孔吸引阴离子通过静电相互作用。我们的工作揭示了以前未知的体积调节阴离子通道的结构和选择性阴离子传导的机制。
Volume-regulated anion channels are activated in response to hypotonic stress. These channels are composed of closely related paralogues of the leucine-rich repeat-containing protein 8 (LRRC8) family that co-assemble to form hexameric complexes. Here, using cryo-electron microscopy and X-ray crystallography, we determine the structure of a homomeric channel of the obligatory subunit LRRC8A. This protein conducts ions and has properties in common with endogenous heteromeric channels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucinerich repeat domain. The transmembrane domain, which is structurally related to connexin proteins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. An excess of basic residues in the filter and throughout the pore attracts anions by electrostatic interaction. Our work reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction.