The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.

The cytoplasmic N-terminal domain of the human ether-a-go-go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N-terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR stru...

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Autores principales:	Chai Ann Ng, Mark J Hunter, Matthew D Perry, Mehdi Mobli, Ying Ke, Philip W Kuchel, Glenn F King, Daniela Stock, Jamie I Vandenberg
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cd58b092df8e48f98ebad7ea3a2f7210
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spelling	oai:doaj.org-article:cd58b092df8e48f98ebad7ea3a2f72102021-11-18T07:00:32ZThe N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.1932-620310.1371/journal.pone.0016191https://doaj.org/article/cd58b092df8e48f98ebad7ea3a2f72102011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21249148/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The cytoplasmic N-terminal domain of the human ether-a-go-go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N-terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N-terminal 135 residues of hERG contains a previously described Per-Arnt-Sim (PAS) domain (residues 26-135) as well as an amphipathic α-helix (residues 13-23) and an initial unstructured segment (residues 2-9). Deletion of residues 2-25, only the unstructured segment (residues 2-9) or replacement of the α-helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α-helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N-terminal α-helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel.Chai Ann NgMark J HunterMatthew D PerryMehdi MobliYing KePhilip W KuchelGlenn F KingDaniela StockJamie I VandenbergPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 1, p e16191 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chai Ann Ng Mark J Hunter Matthew D Perry Mehdi Mobli Ying Ke Philip W Kuchel Glenn F King Daniela Stock Jamie I Vandenberg The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.
description	The cytoplasmic N-terminal domain of the human ether-a-go-go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N-terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N-terminal 135 residues of hERG contains a previously described Per-Arnt-Sim (PAS) domain (residues 26-135) as well as an amphipathic α-helix (residues 13-23) and an initial unstructured segment (residues 2-9). Deletion of residues 2-25, only the unstructured segment (residues 2-9) or replacement of the α-helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α-helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N-terminal α-helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel.
format	article
author	Chai Ann Ng Mark J Hunter Matthew D Perry Mehdi Mobli Ying Ke Philip W Kuchel Glenn F King Daniela Stock Jamie I Vandenberg
author_facet	Chai Ann Ng Mark J Hunter Matthew D Perry Mehdi Mobli Ying Ke Philip W Kuchel Glenn F King Daniela Stock Jamie I Vandenberg
author_sort	Chai Ann Ng
title	The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.
title_short	The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.
title_full	The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.
title_fullStr	The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.
title_full_unstemmed	The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.
title_sort	n-terminal tail of herg contains an amphipathic α-helix that regulates channel deactivation.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/cd58b092df8e48f98ebad7ea3a2f7210
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The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.

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