KCNQ1 potassium channels are essential for physiological processes. Their assembly with KCNE1 generates I Ks currents, which are essential for terminating cardiac action potentials and regulating heart rate. PIP 2 and calmodulin are potent regulators of KCNQ1 activation. KCNQ1 adopts both bent and straight conformations and can transition into intermediate-open (IO) and activated-open (AO) states. Both our recently solved KCNQ1-KCNE1 structure (straight conformation, AO) and KCNQ1-E160R/R231E structure (bent conformation, intermediate-closed, IC) reveal a PIP 2 molecule bound next to the VSD, designated V-PIP 2 . We found that nearly all V-PIP 2 binding site mutants did not reduce KCNQ1 currents (predominantly IO) but did decrease I Ks currents (exclusively AO). Moreover, these mutants almost had no effects on the IO-only mutation (KCNQ1-S338F), while significantly reducing effects on the AO-only mutation (KCNQ1-F351A). Prior studies indicated that V-PIP 2 might compete with calmodulin for VSD binding. Comparison of the AO and IC structures, along with studies of a novel compound (CA1) that specifically enhances I Ks without affecting KCNQ1 function indicates that V-PIP 2 binding changes in response to VSD activation from the I to A state. We employed both metadynamic and targeted MD simulations and found that upward movements of S4 facilitate VSD activation, inducing V-PIP 2 to form closer interactions with the S2-S3 linker and promote calmodulin detachment. Additionally, four interaction pairs between KCNQ1 and calmodulin were identified. Our data collectively support a model in which the channel adopts a bent conformation in the IO state and a straight conformation in the AO state, with V-PIP 2 facilitating the bent-to-straight transition during voltage-dependent VSD activation from the I to A state.
Zhao et al. (Sun,) studied this question.