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.
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.
