Determination of what is the specificity of subunits composing a protein complex is essential when studying gene variants on human pathophysiology. The pore-forming α-subunit KCNQ1, which belongs to the voltage-gated ion channel superfamily, associates to its β-auxiliary subunit KCNE1 to generate the slow cardiac potassium I_Ks current, whose dysfunction leads to cardiac arrhythmia. Using pharmacology, gene invalidation, and single-molecule fluorescence assays, we found that KCNE1 fulfils all criteria of a bona fide auxiliary subunit of the TMEM16A chloride channel, which belongs to the anoctamin superfamily. Strikingly, assembly with KCNE1 switches TMEM16A from a calcium-dependent to a voltage-dependent ion channel. Importantly, clinically relevant inherited mutations within the TMEM16A-regulating domain of KCNE1 abolish the TMEM16A modulation, suggesting that the TMEM16A-KCNE1 current may contribute to inherited pathologies. Altogether, these findings challenge the dogma of the specificity of auxiliary subunits regarding protein complexes and questions ion channel classification.

在研究人类病理生理学的基因变异时，确定组成蛋白质复合物的亚基的特异性是必不可少的。孔形成α-亚基KCNQ1属于电压门控离子通道超家族，与其β-辅助亚基KCNE1结合产生慢速心肌钾I _Ks当前，其功能障碍导致心律失常。使用药理学、基因失效和单分子荧光测定，我们发现 KCNE1 满足 TMEM16A 氯通道真正辅助亚基的所有标准，属于 anoctamin 超家族。引人注目的是，与 KCNE1 的组装将 TMEM16A 从钙依赖性离子通道转换为电压依赖性离子通道。重要的是，KCNE1 的 TMEM16A 调节域内的临床相关遗传突变消除了 TMEM16A 调节，表明 TMEM16A-KCNE1 电流可能导致遗传病状。总之，这些发现挑战了关于蛋白质复合物的辅助亚基特异性的教条，并质疑离子通道分类。