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 c...

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Autores principales:	Olfat A. Malak, Zeineb Es-Salah-Lamoureux, Gildas Loussouarn
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fb63c05f0749402ab82a3705894795ad
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spelling	oai:doaj.org-article:fb63c05f0749402ab82a3705894795ad2021-12-02T11:53:12ZhERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state10.1038/s41598-017-00155-22045-2322https://doaj.org/article/fb63c05f0749402ab82a3705894795ad2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00155-2https://doaj.org/toc/2045-2322Abstract 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-S5L is sufficient to stabilize the pore activation gate in its closed state. Conversely, covalently binding a peptide mimicking S6T to the channel S4-S5L prevents its inhibiting effect and renders the channel almost completely voltage-independent. This shows that the channel S4-S5L is necessary to stabilize the activation gate in its closed state. Altogether, our results provide chemical evidence that S4-S5L acts as a voltage-controlled ligand that binds S6T to 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.Olfat A. MalakZeineb Es-Salah-LamoureuxGildas LoussouarnNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Olfat A. Malak Zeineb Es-Salah-Lamoureux Gildas Loussouarn hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state
description	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-S5L is sufficient to stabilize the pore activation gate in its closed state. Conversely, covalently binding a peptide mimicking S6T to the channel S4-S5L prevents its inhibiting effect and renders the channel almost completely voltage-independent. This shows that the channel S4-S5L is necessary to stabilize the activation gate in its closed state. Altogether, our results provide chemical evidence that S4-S5L acts as a voltage-controlled ligand that binds S6T to 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.
format	article
author	Olfat A. Malak Zeineb Es-Salah-Lamoureux Gildas Loussouarn
author_facet	Olfat A. Malak Zeineb Es-Salah-Lamoureux Gildas Loussouarn
author_sort	Olfat A. Malak
title	hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state
title_short	hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state
title_full	hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state
title_fullStr	hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state
title_full_unstemmed	hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state
title_sort	herg s4-s5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/fb63c05f0749402ab82a3705894795ad
work_keys_str_mv	AT olfatamalak hergs4s5linkeractsasavoltagedependentligandthatbindstotheactivationgateandlocksitinaclosedstate AT zeinebessalahlamoureux hergs4s5linkeractsasavoltagedependentligandthatbindstotheactivationgateandlocksitinaclosedstate AT gildasloussouarn hergs4s5linkeractsasavoltagedependentligandthatbindstotheactivationgateandlocksitinaclosedstate
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hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state

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