Abstract
Long QT syndrome (LQTS) is a heart disorder that can lead to severe cardiac arrhythmias and sudden cardiac death. Hundreds of mutations in the genes (KCNQ1 and KCNE1) encoding the KCNQ1/KCNE1 channel cause LQTS. KCNQ1 contains both a voltage-sensing domain (VSD) and a pore domain (PD). KCNE1 regulates the function of the KCNQ1 channel in several ways. KCNQ1 expressed alone opens when the VSD is in an intermediate state. KCNQ1 co-expressed with KCNE1 opens mainly when the VSD is in a fully activated state. KCNE1 also drastically slows the opening and shifts the voltage dependence of opening by >40 mV of KCNQ1 channels. Using voltage clamp fluorometry, we here show that mutations of conserved residues (F232A and F279A) at the VSD-PD interface alter the VSD-PD coupling so that the mutant KCNQ1/KCNE1 channels open in the intermediate VSD state. The mutant cycle analysis suggested that F232 and F279 are interacting with each other in the KCNQ1 channel only in the presence of KCNE1. Using recent structures of KCNQ1 and KCNE beta subunits in different states, we present a novel mechanism by which KCNE1 rotates the VSD relative to the PD and affects the VSD-PD coupling of KCNQ1 channels in a non-canonical way, forcing KCNQ1/KCNE1 channels to open in the fully-activated VSD state. This would explain many of the KCNE1-induced effects on KCNQ1 channels.