Structural basis of slow gating and arrhythmogenic modulation in the IKs channel complex

Abstract The slowly activating delayed-rectifier K⁺ (IKs) current, generated by the voltage-gated K⁺ channel KCNQ1 and its auxiliary subunit KCNE1, is essential for ventricular repolarization and cardiac rhythm. Mutations in either subunit underlie congenital arrhythmias such as long QT syndrome (LQTS) and atrial fibrillation (AF). However, the structural mechanisms underlying the hallmark slow activation of IKs and its pathological modulation have remained unclear. Here, we present five structures of the human KCNQ1-KCNE1-calmodulin complex: two with the voltage-sensing domain (VSD) in the up and intermediate states, one with an LQTS-associated mutant, and two with AF-associated mutants. Comparison of the VSD-up and intermediate state structures reveals how KCNE1 alters VSD movement and access to the essential lipid ligand PIP₂, providing a structural basis for the slow and positively shifted activation of IKs. Structures of disease-associated mutants show localized conformational changes, offering insight into how these variants perturb gating and contribute to arrhythmogenic phenotypes. Together, our findings establish a framework for understanding the modulation of IKs channel gating in health and disease.