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A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes
Cholesterol controls the activity of a wide range of membrane receptors through specific interactions and identifying cholesterol recognition motifs is therefore critical for understanding signaling receptor function. The membrane-spanning domains of the paradigm neurotransmitter receptor for acetyl...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768152/ https://www.ncbi.nlm.nih.gov/pubmed/26915987 http://dx.doi.org/10.1038/srep21907 |
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author | Fantini, Jacques Di Scala, Coralie Evans, Luke S. Williamson, Philip T. F. Barrantes, Francisco J. |
author_facet | Fantini, Jacques Di Scala, Coralie Evans, Luke S. Williamson, Philip T. F. Barrantes, Francisco J. |
author_sort | Fantini, Jacques |
collection | PubMed |
description | Cholesterol controls the activity of a wide range of membrane receptors through specific interactions and identifying cholesterol recognition motifs is therefore critical for understanding signaling receptor function. The membrane-spanning domains of the paradigm neurotransmitter receptor for acetylcholine (AChR) display a series of cholesterol consensus domains (referred to as “CARC”). Here we use a combination of molecular modeling, lipid monolayer/mutational approaches and NMR spectroscopy to study the binding of cholesterol to a synthetic CARC peptide. The CARC-cholesterol interaction is of high affinity, lipid-specific, concentration-dependent, and sensitive to single-point mutations. The CARC motif is generally located in the outer membrane leaflet and its reverse sequence CRAC in the inner one. Their simultaneous presence within the same transmembrane domain obeys a “mirror code” controlling protein-cholesterol interactions in the outer and inner membrane leaflets. Deciphering this code enabled us to elaborate guidelines for the detection of cholesterol-binding motifs in any membrane protein. Several representative examples of neurotransmitter receptors and ABC transporters with the dual CARC/CRAC motifs are presented. The biological significance and potential clinical applications of the mirror code are discussed. |
format | Online Article Text |
id | pubmed-4768152 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47681522016-03-02 A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes Fantini, Jacques Di Scala, Coralie Evans, Luke S. Williamson, Philip T. F. Barrantes, Francisco J. Sci Rep Article Cholesterol controls the activity of a wide range of membrane receptors through specific interactions and identifying cholesterol recognition motifs is therefore critical for understanding signaling receptor function. The membrane-spanning domains of the paradigm neurotransmitter receptor for acetylcholine (AChR) display a series of cholesterol consensus domains (referred to as “CARC”). Here we use a combination of molecular modeling, lipid monolayer/mutational approaches and NMR spectroscopy to study the binding of cholesterol to a synthetic CARC peptide. The CARC-cholesterol interaction is of high affinity, lipid-specific, concentration-dependent, and sensitive to single-point mutations. The CARC motif is generally located in the outer membrane leaflet and its reverse sequence CRAC in the inner one. Their simultaneous presence within the same transmembrane domain obeys a “mirror code” controlling protein-cholesterol interactions in the outer and inner membrane leaflets. Deciphering this code enabled us to elaborate guidelines for the detection of cholesterol-binding motifs in any membrane protein. Several representative examples of neurotransmitter receptors and ABC transporters with the dual CARC/CRAC motifs are presented. The biological significance and potential clinical applications of the mirror code are discussed. Nature Publishing Group 2016-02-26 /pmc/articles/PMC4768152/ /pubmed/26915987 http://dx.doi.org/10.1038/srep21907 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Fantini, Jacques Di Scala, Coralie Evans, Luke S. Williamson, Philip T. F. Barrantes, Francisco J. A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes |
title | A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes |
title_full | A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes |
title_fullStr | A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes |
title_full_unstemmed | A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes |
title_short | A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes |
title_sort | mirror code for protein-cholesterol interactions in the two leaflets of biological membranes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768152/ https://www.ncbi.nlm.nih.gov/pubmed/26915987 http://dx.doi.org/10.1038/srep21907 |
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