A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia

Abstract Channelopathy mutations prove informative on disease causing mechanisms and channel gating dynamics. We have identified a novel heterozygous mutation in the KCNA1 gene of a young proband displaying typical signs and symptoms of Episodic Ataxia type 1 (EA1). This mutation is in the S4 helix...

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Autores principales:	Sonia Hasan, Cecilia Bove, Gabriella Silvestri, Elide Mantuano, Anna Modoni, Liana Veneziano, Lara Macchioni, Therese Hunter, Gary Hunter, Mauro Pessia, Maria Cristina D’Adamo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/02ddbd2c1d7742bb819b694818c46801
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spelling	oai:doaj.org-article:02ddbd2c1d7742bb819b694818c468012021-12-02T16:06:42ZA channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia10.1038/s41598-017-03041-z2045-2322https://doaj.org/article/02ddbd2c1d7742bb819b694818c468012017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03041-zhttps://doaj.org/toc/2045-2322Abstract Channelopathy mutations prove informative on disease causing mechanisms and channel gating dynamics. We have identified a novel heterozygous mutation in the KCNA1 gene of a young proband displaying typical signs and symptoms of Episodic Ataxia type 1 (EA1). This mutation is in the S4 helix of the voltage-sensing domain and results in the substitution of the highly conserved phenylalanine 303 by valine (p.F303V). The contributions of F303 towards K+ channel voltage gating are unclear and here have been assessed biophysically and by performing structural analysis using rat Kv1.2 coordinates. We observed significant positive shifts of voltage-dependence, changes in the activation, deactivation and slow inactivation kinetics, reduced window currents, and decreased current amplitudes of both Kv1.1 and Kv1.1/1.2 channels. Structural analysis revealed altered interactions between F303V and L339 and I335 of the S5 helix of a neighboring subunit. The substitution of an aromatic phenylalanine with an aliphatic valine within the voltage-sensor destabilizes the open state of the channel. Thus, F303 fine-tunes the Kv1.1 gating properties and contributes to the interactions between the S4 segment and neighboring alpha helices. The resulting channel’s loss of function validates the clinical relevance of the mutation for EA1 pathogenesis.Sonia HasanCecilia BoveGabriella SilvestriElide MantuanoAnna ModoniLiana VenezianoLara MacchioniTherese HunterGary HunterMauro PessiaMaria Cristina D’AdamoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sonia Hasan Cecilia Bove Gabriella Silvestri Elide Mantuano Anna Modoni Liana Veneziano Lara Macchioni Therese Hunter Gary Hunter Mauro Pessia Maria Cristina D’Adamo A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia
description	Abstract Channelopathy mutations prove informative on disease causing mechanisms and channel gating dynamics. We have identified a novel heterozygous mutation in the KCNA1 gene of a young proband displaying typical signs and symptoms of Episodic Ataxia type 1 (EA1). This mutation is in the S4 helix of the voltage-sensing domain and results in the substitution of the highly conserved phenylalanine 303 by valine (p.F303V). The contributions of F303 towards K+ channel voltage gating are unclear and here have been assessed biophysically and by performing structural analysis using rat Kv1.2 coordinates. We observed significant positive shifts of voltage-dependence, changes in the activation, deactivation and slow inactivation kinetics, reduced window currents, and decreased current amplitudes of both Kv1.1 and Kv1.1/1.2 channels. Structural analysis revealed altered interactions between F303V and L339 and I335 of the S5 helix of a neighboring subunit. The substitution of an aromatic phenylalanine with an aliphatic valine within the voltage-sensor destabilizes the open state of the channel. Thus, F303 fine-tunes the Kv1.1 gating properties and contributes to the interactions between the S4 segment and neighboring alpha helices. The resulting channel’s loss of function validates the clinical relevance of the mutation for EA1 pathogenesis.
format	article
author	Sonia Hasan Cecilia Bove Gabriella Silvestri Elide Mantuano Anna Modoni Liana Veneziano Lara Macchioni Therese Hunter Gary Hunter Mauro Pessia Maria Cristina D’Adamo
author_facet	Sonia Hasan Cecilia Bove Gabriella Silvestri Elide Mantuano Anna Modoni Liana Veneziano Lara Macchioni Therese Hunter Gary Hunter Mauro Pessia Maria Cristina D’Adamo
author_sort	Sonia Hasan
title	A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia
title_short	A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia
title_full	A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia
title_fullStr	A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia
title_full_unstemmed	A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia
title_sort	channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of kv1.1 channels and ataxia
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/02ddbd2c1d7742bb819b694818c46801
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A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia

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