PIP(2)-dependent coupling of voltage sensor and pore domains in K(v)7.2 channel

Phosphatidylinositol-4,5-bisphosphate (PIP(2)) is a signaling lipid which regulates voltage-gated K(v)7/KCNQ potassium channels. Altered PIP(2) sensitivity of neuronal K(v)7.2 channel is involved in KCNQ2 epileptic encephalopathy. However, the molecular action of PIP(2) on K(v)7.2 gating remains largely elusive. Here, we use molecular dynamics simulations and electrophysiology to characterize PIP(2) binding sites in a human K(v)7.2 channel. In the closed state, PIP(2) localizes to the periphery of the voltage-sensing domain (VSD). In the open state, PIP(2) binds to 4 distinct interfaces formed by the cytoplasmic ends of the VSD, the gate, intracellular helices A and B and their linkers. PIP(2) binding induces bilayer-interacting conformation of helices A and B and the correlated motion of the VSD and the pore domain, whereas charge-neutralizing mutations block this coupling and reduce PIP(2) sensitivity of K(v)7.2 channels by disrupting PIP(2) binding. These findings reveal the allosteric role of PIP(2) in K(v)7.2 channel activation.