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Intrinsically disordered ectodomain modulates ion permeation through a metal transporter

The function of many channels and transporters is enriched by the conformational plasticity of intrinsically disordered regions (IDRs). Copper transporter 1 (Ctr1) is the main entry point for Cu(I) ions in eukaryotes and contains IDRs both at its N-terminal (Nterm) and C-terminal ends. The former de...

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Autores principales: Aupič, Jana, Lapenta, Fabio, Janoš, Pavel, Magistrato, Alessandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9889885/
https://www.ncbi.nlm.nih.gov/pubmed/36409899
http://dx.doi.org/10.1073/pnas.2214602119
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author Aupič, Jana
Lapenta, Fabio
Janoš, Pavel
Magistrato, Alessandra
author_facet Aupič, Jana
Lapenta, Fabio
Janoš, Pavel
Magistrato, Alessandra
author_sort Aupič, Jana
collection PubMed
description The function of many channels and transporters is enriched by the conformational plasticity of intrinsically disordered regions (IDRs). Copper transporter 1 (Ctr1) is the main entry point for Cu(I) ions in eukaryotes and contains IDRs both at its N-terminal (Nterm) and C-terminal ends. The former delivers copper ions from the extracellular matrix to the selectivity filter in the Ctr1 lumen. However, the molecular mechanism of this process remains elusive due to Nterm’s disordered nature. Here, we combine advanced molecular dynamics simulations and circular dichroism experiments to show that Cu(I) ions and a lipidic environment drive the insertion of the Nterm into the Ctr1 selectivity filter, causing its opening. Through a lipid-aided conformational switch of one of the transmembrane helices, the conformational change of the selectivity filter propagates down to the cytosolic gate of Ctr1. Taken together, our results elucidate how conformational variability of IDRs modulates ion transport.
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spelling pubmed-98898852023-05-21 Intrinsically disordered ectodomain modulates ion permeation through a metal transporter Aupič, Jana Lapenta, Fabio Janoš, Pavel Magistrato, Alessandra Proc Natl Acad Sci U S A Biological Sciences The function of many channels and transporters is enriched by the conformational plasticity of intrinsically disordered regions (IDRs). Copper transporter 1 (Ctr1) is the main entry point for Cu(I) ions in eukaryotes and contains IDRs both at its N-terminal (Nterm) and C-terminal ends. The former delivers copper ions from the extracellular matrix to the selectivity filter in the Ctr1 lumen. However, the molecular mechanism of this process remains elusive due to Nterm’s disordered nature. Here, we combine advanced molecular dynamics simulations and circular dichroism experiments to show that Cu(I) ions and a lipidic environment drive the insertion of the Nterm into the Ctr1 selectivity filter, causing its opening. Through a lipid-aided conformational switch of one of the transmembrane helices, the conformational change of the selectivity filter propagates down to the cytosolic gate of Ctr1. Taken together, our results elucidate how conformational variability of IDRs modulates ion transport. National Academy of Sciences 2022-11-21 2022-11-29 /pmc/articles/PMC9889885/ /pubmed/36409899 http://dx.doi.org/10.1073/pnas.2214602119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Aupič, Jana
Lapenta, Fabio
Janoš, Pavel
Magistrato, Alessandra
Intrinsically disordered ectodomain modulates ion permeation through a metal transporter
title Intrinsically disordered ectodomain modulates ion permeation through a metal transporter
title_full Intrinsically disordered ectodomain modulates ion permeation through a metal transporter
title_fullStr Intrinsically disordered ectodomain modulates ion permeation through a metal transporter
title_full_unstemmed Intrinsically disordered ectodomain modulates ion permeation through a metal transporter
title_short Intrinsically disordered ectodomain modulates ion permeation through a metal transporter
title_sort intrinsically disordered ectodomain modulates ion permeation through a metal transporter
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9889885/
https://www.ncbi.nlm.nih.gov/pubmed/36409899
http://dx.doi.org/10.1073/pnas.2214602119
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