KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies

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