Key result
Molecular simulations identify 9 residues driving the interaction between PIP2 and Kv7.1/KCNE1.
Identified nine key residues forming binding pockets for PIP2 on Kv7.1/KCNE1 channels, providing structural insights into channel regulation and potential mechanisms of long QT syndrome.
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Does not alter clinical management of long QT syndrome; extends structural mapping of PIP2 sites on Kv7.1/KCNE1 in preclinical models.
Kv7.1 to Kv7.5 α-subunits belong to the family of voltage-gated potassium channels (Kv). Assembled with the β-subunit KCNE1, Kv7.1 conducts the slowly activating potassium current IKs, which is one of the major currents underlying repolarization of the cardiac action potential. A known regulator of Kv7 channels is the lipid phosphatidylinositol 4,5-bisphosphate (PIP2). PIP2 increases the macroscopic current amplitude by stabilizing the open conformation of 7.1/KCNE1 channels. However, knowledge about the exact nature of the interaction is incomplete. The aim of this study was the identification of the amino acids responsible for the interaction between Kv7.1 and PIP2. We generated 13 charge neutralizing point mutations at the intracellular membrane border and characterized them electrophysiologically in complex with KCNE1 under the influence of diC8-PIP2. Electrophysiological analysis of corresponding long QT syndrome mutants suggested impaired PIP2 regulation as the cause for channel dysfunction. To clarify the underlying structural mechanism of PIP2 binding, molecular dynamics simulations of Kv7.1/KCNE1 complexes containing two PIP2 molecules in each subunit at specific sites were performed. Here, we identified a subset of nine residues participating in the interaction of PIP2 and Kv7.1/KCNE1. These residues may form at least two binding pockets per subunit, leading to the stabilization of channel conformations upon PIP2 binding.
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Eckey et al. (2014) studied Long QT syndrome. Charge neutralizing point mutations and molecular dynamics simulations was evaluated on Identification of amino acids responsible for interaction between Kv7.1 and PIP2. Charge neutralization scanning and molecular dynamics simulations identified nine residues participating in the interaction of PIP2 and Kv7.1/KCNE1, forming at least two binding pockets per subunit.
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