Mutagenesis and molecular dynamics simulations identified a noncanonical electromechanical coupling path involving the S4/S1 and S1/S5 subunit interfaces that is crucial for hERG channel activation and inactivation.
Demonstrates a noncanonical electromechanical transduction path crucial for the gating of the cardiac hERG potassium channel.
Abstract Voltage-gated potassium channels are involved in many physiological processes such as nerve impulse transmission, the heartbeat, and muscle contraction. However, for many of them the molecular determinants of the gating mechanism remain elusive. Here, using a combination of theoretical and experimental approaches, we address this problem focusing on the cardiac hERG potassium channel. Network analysis of molecular dynamics trajectories reveals the presence of a kinematic chain of residues that couples the voltage sensor domain to the pore domain and involves the S4/S1 and S1/S5 subunit interfaces. Mutagenesis experiments confirm the role of these residues and interfaces in the activation and inactivation mechanisms. Our findings demonstrate the presence of an electromechanical transduction path crucial for the non-domain-swapped hERG channel gating that resembles the noncanonical path identified in domain-swapped K + channels.
Bassetto et al. (2023) studied hERG potassium channel gating. Site-directed mutagenesis (leucine-scanning) vs. Wild-type hERG channel was evaluated on Voltage dependence of activation and inactivation (V1/2 and free-energy perturbation). Mutagenesis and molecular dynamics simulations identified a noncanonical electromechanical coupling path involving the S4/S1 and S1/S5 subunit interfaces that is crucial for hERG channel activation and inactivation.