title: hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state.
abstract: Delayed-rectifier potassium channels (hERG and KCNQ1) play a major role in cardiac repolarization. These channels are formed by a tetrameric pore (S5-S6) surrounded by four voltage sensor domains (S1-S4). Coupling between voltage sensor domains and the pore activation gate is critical for channel voltage-dependence. However, molecular mechanisms remain elusive. Herein, we demonstrate that covalently binding, through a disulfide bridge, a peptide mimicking the S4-S5 linker (S4-S5L) to the channel S6 C-terminus (S6T) completely inhibits hERG. This shows that channel S4-S5Lis sufficient to stabilize the pore activation gate in its closed state. Conversely, covalently binding a peptide mimicking S6Tto the channel S4-S5Lprevents its inhibiting effect and renders the channel almost completely voltage-independent. This shows that the channel S4-S5Lis necessary to stabilize the activation gate in its closed state. Altogether, our results provide chemical evidence that S4-S5Lacts as a voltage-controlled ligand that binds S6Tto lock the channel in a closed state, elucidating the coupling between voltage sensors and the gate in delayed rectifier potassium channels and potentially other voltage-gated channels.
authors.affiliation: INSERM, CNRS, l'Institut du Thorax, Université de Nantes, 44007, Nantes, France.
authors.forename: Olfat A
authors.initials: OA
authors.lastname: Malak
authors.affiliation: INSERM, CNRS, l'Institut du Thorax, Université de Nantes, 44007, Nantes, France.
authors.forename: Zeineb
authors.initials: Z
authors.lastname: Es-Salah-Lamoureux
authors.affiliation: INSERM, CNRS, l'Institut du Thorax, Université de Nantes, 44007, Nantes, France. gildas.loussouarn@inserm.fr.
authors.forename: Gildas
authors.identifier: 0000-0001-8007-5931
authors.initials: G
authors.lastname: Loussouarn