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Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca(2+)-bound nhTMEM16
Both lipid and ion translocation by Ca(2+)-regulated TMEM16 transmembrane proteins utilizes a membrane-exposed hydrophilic groove. Several conformations of the groove are observed in TMEM16 protein structures, but how these conformations form, and what functions they support, remains unknown. From a...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823365/ https://www.ncbi.nlm.nih.gov/pubmed/31672969 http://dx.doi.org/10.1038/s41467-019-12865-4 |
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author | Khelashvili, George Falzone, Maria E. Cheng, Xiaolu Lee, Byoung-Cheol Accardi, Alessio Weinstein, Harel |
author_facet | Khelashvili, George Falzone, Maria E. Cheng, Xiaolu Lee, Byoung-Cheol Accardi, Alessio Weinstein, Harel |
author_sort | Khelashvili, George |
collection | PubMed |
description | Both lipid and ion translocation by Ca(2+)-regulated TMEM16 transmembrane proteins utilizes a membrane-exposed hydrophilic groove. Several conformations of the groove are observed in TMEM16 protein structures, but how these conformations form, and what functions they support, remains unknown. From analyses of atomistic molecular dynamics simulations of Ca(2+)-bound nhTMEM16 we find that the mechanism of a conformational transition of the groove from membrane-exposed to occluded from the membrane involves the repositioning of transmembrane helix 4 (TM4) following its disengagement from a TM3/TM4 interaction interface. Residue L302 is a key element in the hydrophobic TM3/TM4 interaction patch that braces the open-groove conformation, which should be changed by an L302A mutation. The structure of the L302A mutant determined by cryogenic electron microscopy (cryo-EM) reveals a partially closed groove that could translocate ions, but not lipids. This is corroborated with functional assays showing severely impaired lipid scrambling, but robust channel activity by L302A. |
format | Online Article Text |
id | pubmed-6823365 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68233652019-11-04 Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca(2+)-bound nhTMEM16 Khelashvili, George Falzone, Maria E. Cheng, Xiaolu Lee, Byoung-Cheol Accardi, Alessio Weinstein, Harel Nat Commun Article Both lipid and ion translocation by Ca(2+)-regulated TMEM16 transmembrane proteins utilizes a membrane-exposed hydrophilic groove. Several conformations of the groove are observed in TMEM16 protein structures, but how these conformations form, and what functions they support, remains unknown. From analyses of atomistic molecular dynamics simulations of Ca(2+)-bound nhTMEM16 we find that the mechanism of a conformational transition of the groove from membrane-exposed to occluded from the membrane involves the repositioning of transmembrane helix 4 (TM4) following its disengagement from a TM3/TM4 interaction interface. Residue L302 is a key element in the hydrophobic TM3/TM4 interaction patch that braces the open-groove conformation, which should be changed by an L302A mutation. The structure of the L302A mutant determined by cryogenic electron microscopy (cryo-EM) reveals a partially closed groove that could translocate ions, but not lipids. This is corroborated with functional assays showing severely impaired lipid scrambling, but robust channel activity by L302A. Nature Publishing Group UK 2019-10-31 /pmc/articles/PMC6823365/ /pubmed/31672969 http://dx.doi.org/10.1038/s41467-019-12865-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Khelashvili, George Falzone, Maria E. Cheng, Xiaolu Lee, Byoung-Cheol Accardi, Alessio Weinstein, Harel Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca(2+)-bound nhTMEM16 |
title | Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca(2+)-bound nhTMEM16 |
title_full | Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca(2+)-bound nhTMEM16 |
title_fullStr | Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca(2+)-bound nhTMEM16 |
title_full_unstemmed | Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca(2+)-bound nhTMEM16 |
title_short | Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca(2+)-bound nhTMEM16 |
title_sort | dynamic modulation of the lipid translocation groove generates a conductive ion channel in ca(2+)-bound nhtmem16 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823365/ https://www.ncbi.nlm.nih.gov/pubmed/31672969 http://dx.doi.org/10.1038/s41467-019-12865-4 |
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