Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter

Abstract Two-pore domain potassium (K2P) channel ion conductance is regulated by diverse stimuli that directly or indirectly gate the channel selectivity filter (SF). Recent crystal structures for the TREK-2 member of the K2P family reveal distinct “up” and “down” states assumed during activation vi...

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Autores principales:	Matthew P. Harrigan, Keri A. McKiernan, Veerabahu Shanmugasundaram, Rajiah Aldrin Denny, Vijay S. Pande
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dd1ffd3260654a00bc7579dd22c01274
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spelling	oai:doaj.org-article:dd1ffd3260654a00bc7579dd22c012742021-12-02T16:07:59ZMarkov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter10.1038/s41598-017-00256-y2045-2322https://doaj.org/article/dd1ffd3260654a00bc7579dd22c012742017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00256-yhttps://doaj.org/toc/2045-2322Abstract Two-pore domain potassium (K2P) channel ion conductance is regulated by diverse stimuli that directly or indirectly gate the channel selectivity filter (SF). Recent crystal structures for the TREK-2 member of the K2P family reveal distinct “up” and “down” states assumed during activation via mechanical stretch. We performed 195 μs of all-atom, unbiased molecular dynamics simulations of the TREK-2 channel to probe how membrane stretch regulates the SF gate. Markov modeling reveals a novel “pinched” SF configuration that stretch activation rapidly destabilizes. Free-energy barrier heights calculated for critical steps in the conduction pathway indicate that this pinched state impairs ion conduction. Our simulations predict that this low-conductance state is accessed exclusively in the compressed, “down” conformation in which the intracellular helix arrangement allosterically pinches the SF. By explicitly relating structure to function, we contribute a critical piece of understanding to the evolving K2P puzzle.Matthew P. HarriganKeri A. McKiernanVeerabahu ShanmugasundaramRajiah Aldrin DennyVijay S. PandeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matthew P. Harrigan Keri A. McKiernan Veerabahu Shanmugasundaram Rajiah Aldrin Denny Vijay S. Pande Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter
description	Abstract Two-pore domain potassium (K2P) channel ion conductance is regulated by diverse stimuli that directly or indirectly gate the channel selectivity filter (SF). Recent crystal structures for the TREK-2 member of the K2P family reveal distinct “up” and “down” states assumed during activation via mechanical stretch. We performed 195 μs of all-atom, unbiased molecular dynamics simulations of the TREK-2 channel to probe how membrane stretch regulates the SF gate. Markov modeling reveals a novel “pinched” SF configuration that stretch activation rapidly destabilizes. Free-energy barrier heights calculated for critical steps in the conduction pathway indicate that this pinched state impairs ion conduction. Our simulations predict that this low-conductance state is accessed exclusively in the compressed, “down” conformation in which the intracellular helix arrangement allosterically pinches the SF. By explicitly relating structure to function, we contribute a critical piece of understanding to the evolving K2P puzzle.
format	article
author	Matthew P. Harrigan Keri A. McKiernan Veerabahu Shanmugasundaram Rajiah Aldrin Denny Vijay S. Pande
author_facet	Matthew P. Harrigan Keri A. McKiernan Veerabahu Shanmugasundaram Rajiah Aldrin Denny Vijay S. Pande
author_sort	Matthew P. Harrigan
title	Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter
title_short	Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter
title_full	Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter
title_fullStr	Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter
title_full_unstemmed	Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter
title_sort	markov modeling reveals novel intracellular modulation of the human trek-2 selectivity filter
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/dd1ffd3260654a00bc7579dd22c01274
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_version_	1718384687912583168

Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter

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