PIP2 binding at the voltage sensor domain facilitates KCNQ1 VSD activation and gating.

Abstract

The cardiac KCNQ1 channel is involved in cell hyperpolarisation, and loss-of-function mutations are associated with Long QT syndrome (LQTS), which can cause sudden cardiac arrest. The KCNQ1 channel is gated by the changes in transmembrane voltage and crucially requires the binding of two phosphatidylinositol-4,5-bisphosphate (PIP2) molecules to open the channel. The recent structure of KCNQ1 has revealed a PIP2 binding site at the voltage-sensor domain (VSD). In addition, previous modelling and electrophysiological studies have proposed another PIP2 binding site at the pore domain. Using enhanced sampling molecular dynamics simulation, we show that PIP2 binding at the VSD facilitates its activation, whereas PIP2 interaction of the pore facilitates VSD-pore coupling by straightening the S6 helix. Our simulation proposes that PIP2 binding at the VSD acts as a counter charge pausing point during the voltage-dependent activation process, lowering the energy barrier during the S4 translocation. Together, our work highlights the importance of PIP2 at the VSD as an activator to the VSD activation, in addition to our previous knowledge as the key coupler between the VSD and the pore.