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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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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. |
format | Online Article Text |
id | pubmed-9889885 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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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