BPS2026 - Secondary structure transitions define cardiac KCNQ1-KCNE1 channel gating

The KCNQ1+KCNE1 (IKs) potassium channel is essential for cardiac repolarization, and its loss-of-function mutations cause long QT syndrome types 1 and 5. While KCNE1 binding dramatically slows KCNQ1 activation, a key feature enabling IKs's role in action potential repolarization, the structural basis for this slow activation has been unknown. Using cryo-EM and electrophysiology, we determined high-resolution structures of human KCNQ1 and the KCNQ1+KCNE1 complex in closed and open states. KCNE1 binds at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1’s transmembrane segments. Three of these surrounding the S4-S5 linker remain as loops during gating, while three others in S6 and helix A are dynamic. These structural rearrangements (1) stabilize the closed pore and the intermediate VSD, thereby determining channel gating, ion permeation, and single channel conductance; (2) enable a dual-PIP2 modulation mechanism, where one occupies the canonical site, the second bridges the S4-S5 linker, KCNE1, and the adjacent S6’, stabilizing channel opening; and (3) create a fenestration capable of binding KCNQ1+KCNE1-specific compounds (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes I Ks function and provides a foundation for targeted LQTS therapy development.