TMEM206 has been recently identified as an evolutionarily conserved chloride channel that underlies ubiquitously expressed, proton-activated, outwardly rectifying anion currents. Here, we report the cryo–electron microscopy structure of pufferfish TMEM206, which forms a trimeric channel, with each subunit comprising two transmembrane segments and a large extracellular domain. An ample vestibule in the extracellular region is accessible laterally from the three side portals. The central pore contains multiple constrictions. A conserved lysine residue near the cytoplasmic end of the inner helix forms the presumed chloride ion selectivity filter. Unprecedentedly, the core structure and assembly closely resemble those of the epithelial sodium channel/degenerin family of sodium channels that are unrelated in amino acid sequence and conduct cations instead of anions. Together with electrophysiology, this work provides insights into ion conduction and gating for a new class of chloride channels that is architecturally distinct from previously characterized chloride channel families.

TMEM206 最近被确定为一种进化上保守的氯离子通道，它是普遍表达的、质子激活的、向外整流的阴离子电流的基础。在这里，我们报告了河豚 TMEM206 的低温电子显微镜结构，它形成了一个三聚体通道，每个亚基包含两个跨膜片段和一个大的细胞外结构域。细胞外区域的宽敞前庭可从三个侧入口横向进入。中央孔包含多个收缩。靠近内螺旋细胞质末端的保守赖氨酸残基形成假定的氯离子选择性过滤器。前所未有地，核心结构和组装与上皮钠通道/钠通道退化蛋白家族的核心结构和组装非常相似，这些钠通道在氨基酸序列上不相关并且传导阳离子而不是阴离子。与电生理学一起，这项工作提供了对离子传导和门控的新一类氯离子通道的见解，该氯离子通道在结构上不同于先前表征的氯离子通道家族。