Department of Biochemistry, University of Zurich, Zurich, Switzerland.
Department of Structural Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
Nature. 2018 Jun;558(7709):254-259. doi: 10.1038/s41586-018-0134-y. Epub 2018 May 16.
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 leucine-rich 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.
容积调节阴离子通道在应对低渗应激时被激活。这些通道由富含亮氨酸重复序列的蛋白质 8（LRRC8）家族的密切相关的同源物组成，它们共同组装形成六聚体复合物。在这里，我们使用冷冻电子显微镜和 X 射线晶体学来确定必需亚基 LRRC8A 的同源通道的结构。这种蛋白质传导离子，并且具有与内源性杂合通道共同的特性。其模块化结构由跨膜孔结构域和细胞质富含亮氨酸重复结构域组成。跨膜结构域在结构上与连接蛋白相关，朝向细胞质的一侧较宽，但在外侧被一个作为选择性过滤器的结构单元限制。过滤器和整个孔中的大量碱性残基通过静电相互作用吸引阴离子。我们的工作揭示了容积调节阴离子通道的先前未知的结构及其选择性阴离子传导的机制。
