PIP-dependent coupling of voltage sensor and pore domains in K7.2 channel.

Phosphatidylinositol-4,5-bisphosphate (PIP) is a signaling lipid which regulates voltage-gated K7/KCNQ potassium channels. Altered PIP sensitivity of neuronal K7.2 channel is involved in KCNQ2 epileptic encephalopathy. However, the molecular action of PIP on K7.2 gating remains largely elusive. Here, we use molecular dynamics simulations and electrophysiology to characterize PIP binding sites in a human K7.2 channel. In the closed state, PIP localizes to the periphery of the voltage-sensing domain (VSD). In the open state, PIP binds to 4 distinct interfaces formed by the cytoplasmic ends of the VSD, the gate, intracellular helices A and B and their linkers. PIP 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 sensitivity of K7.2 channels by disrupting PIP binding. These findings reveal the allosteric role of PIP in K7.2 channel activation.