Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function

Abstract Although transmembrane helix-helix interactions must be strong enough to drive folding, they must still permit the inter-helix movements associated with conformational change. Interactions between the outermost M4 and adjacent M1 and M3 α-helices of pentameric ligand-gated ion channels have...

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Autores principales:	J. P. Daniel Therien, John E. Baenziger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/362d64d22acc4e0e91ba4a148bdf5266
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spelling	oai:doaj.org-article:362d64d22acc4e0e91ba4a148bdf52662021-12-02T16:06:42ZPentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function10.1038/s41598-017-00573-22045-2322https://doaj.org/article/362d64d22acc4e0e91ba4a148bdf52662017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00573-2https://doaj.org/toc/2045-2322Abstract Although transmembrane helix-helix interactions must be strong enough to drive folding, they must still permit the inter-helix movements associated with conformational change. Interactions between the outermost M4 and adjacent M1 and M3 α-helices of pentameric ligand-gated ion channels have been implicated in folding and function. Here, we evaluate the role of different physical interactions at this interface in the function of two prokaryotic homologs, GLIC and ELIC. Strikingly, disruption of most interactions in GLIC lead to either a reduction or a complete loss of expression and/or function, while analogous disruptions in ELIC often lead to gains in function. Structural comparisons suggest that GLIC and ELIC represent distinct transmembrane domain archetypes. One archetype, exemplified by GLIC, the glycine and GABA receptors and the glutamate activated chloride channel, has extensive aromatic contacts that govern M4-M1/M3 interactions and that are essential for expression and function. The other archetype, exemplified by ELIC and both the nicotinic acetylcholine and serotonin receptors, has relatively few aromatic contacts that are detrimental to function. These archetypes likely have evolved different mechanisms to balance the need for strong M4 “binding” to M1/M3 to promote folding/expression, and the need for weaker interactions that allow for greater conformational flexibility.J. P. Daniel TherienJohn E. BaenzigerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q J. P. Daniel Therien John E. Baenziger Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function
description	Abstract Although transmembrane helix-helix interactions must be strong enough to drive folding, they must still permit the inter-helix movements associated with conformational change. Interactions between the outermost M4 and adjacent M1 and M3 α-helices of pentameric ligand-gated ion channels have been implicated in folding and function. Here, we evaluate the role of different physical interactions at this interface in the function of two prokaryotic homologs, GLIC and ELIC. Strikingly, disruption of most interactions in GLIC lead to either a reduction or a complete loss of expression and/or function, while analogous disruptions in ELIC often lead to gains in function. Structural comparisons suggest that GLIC and ELIC represent distinct transmembrane domain archetypes. One archetype, exemplified by GLIC, the glycine and GABA receptors and the glutamate activated chloride channel, has extensive aromatic contacts that govern M4-M1/M3 interactions and that are essential for expression and function. The other archetype, exemplified by ELIC and both the nicotinic acetylcholine and serotonin receptors, has relatively few aromatic contacts that are detrimental to function. These archetypes likely have evolved different mechanisms to balance the need for strong M4 “binding” to M1/M3 to promote folding/expression, and the need for weaker interactions that allow for greater conformational flexibility.
format	article
author	J. P. Daniel Therien John E. Baenziger
author_facet	J. P. Daniel Therien John E. Baenziger
author_sort	J. P. Daniel Therien
title	Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function
title_short	Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function
title_full	Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function
title_fullStr	Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function
title_full_unstemmed	Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function
title_sort	pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/362d64d22acc4e0e91ba4a148bdf5266
work_keys_str_mv	AT jpdanieltherien pentamericligandgatedionchannelsexhibitdistincttransmembranedomainarchetypesforfoldingexpressionandfunction AT johnebaenziger pentamericligandgatedionchannelsexhibitdistincttransmembranedomainarchetypesforfoldingexpressionandfunction
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Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function

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