TCB Publications - Abstract

Shashank Pant, Jiaren Zhang, Eung Kim, Kin Lam, Hee Jung Chung, and Emad Tajkhorshid. PIP2-dependent coupling of voltage sensor and pore domains in Kv7.2. Communications Biology, 4, 2021. Published.

PANT2021-ET Phosphatidylinositol-4,5-bisphosphate (PIP_2) is a signaling lipid which regulates voltage-gated K_v7/KCNQ potassium channels. Altered PIP_2 sensitivity of neuronal K_v7.2 channel is involved in KCNQ2 epileptic encephalopathy. However, the molecular action of PIP_2 on K_v7.2 gating remains largely elusive. Here, we use molecular dynamics simulations and electrophysiology to characterize PIP_2 binding sites in a human K_v7.2 channel. In the closed state, PIP2 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_v7.2 channels by disrupting PIP_2 binding. These findings reveal the allosteric role of PIP_2 in K_v7.2 channel activation.

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