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The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics
The human cathelicidin LL-37 serves a critical role in the innate immune system defending bacterial infections. LL-37 can interact with molecules of the cell wall and perforate cytoplasmic membranes resulting in bacterial cell death. To test the interactions of LL-37 and bacterial cell wall componen...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562864/ https://www.ncbi.nlm.nih.gov/pubmed/33060695 http://dx.doi.org/10.1038/s41598-020-74401-5 |
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author | Sancho-Vaello, Enea Gil-Carton, David François, Patrice Bonetti, Eve-Julie Kreir, Mohamed Pothula, Karunakar Reddy Kleinekathöfer, Ulrich Zeth, Kornelius |
author_facet | Sancho-Vaello, Enea Gil-Carton, David François, Patrice Bonetti, Eve-Julie Kreir, Mohamed Pothula, Karunakar Reddy Kleinekathöfer, Ulrich Zeth, Kornelius |
author_sort | Sancho-Vaello, Enea |
collection | PubMed |
description | The human cathelicidin LL-37 serves a critical role in the innate immune system defending bacterial infections. LL-37 can interact with molecules of the cell wall and perforate cytoplasmic membranes resulting in bacterial cell death. To test the interactions of LL-37 and bacterial cell wall components we crystallized LL-37 in the presence of detergents and obtained the structure of a narrow tetrameric channel with a strongly charged core. The formation of a tetramer was further studied by cross-linking in the presence of detergents and lipids. Using planar lipid membranes a small but defined conductivity of this channel could be demonstrated. Molecular dynamic simulations underline the stability of this channel in membranes and demonstrate pathways for the passage of water molecules. Time lapse studies of E. coli cells treated with LL-37 show membrane discontinuities in the outer membrane followed by cell wall damage and cell death. Collectively, our results open a venue to the understanding of a novel AMP killing mechanism and allows the rational design of LL-37 derivatives with enhanced bactericidal activity. |
format | Online Article Text |
id | pubmed-7562864 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75628642020-10-19 The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics Sancho-Vaello, Enea Gil-Carton, David François, Patrice Bonetti, Eve-Julie Kreir, Mohamed Pothula, Karunakar Reddy Kleinekathöfer, Ulrich Zeth, Kornelius Sci Rep Article The human cathelicidin LL-37 serves a critical role in the innate immune system defending bacterial infections. LL-37 can interact with molecules of the cell wall and perforate cytoplasmic membranes resulting in bacterial cell death. To test the interactions of LL-37 and bacterial cell wall components we crystallized LL-37 in the presence of detergents and obtained the structure of a narrow tetrameric channel with a strongly charged core. The formation of a tetramer was further studied by cross-linking in the presence of detergents and lipids. Using planar lipid membranes a small but defined conductivity of this channel could be demonstrated. Molecular dynamic simulations underline the stability of this channel in membranes and demonstrate pathways for the passage of water molecules. Time lapse studies of E. coli cells treated with LL-37 show membrane discontinuities in the outer membrane followed by cell wall damage and cell death. Collectively, our results open a venue to the understanding of a novel AMP killing mechanism and allows the rational design of LL-37 derivatives with enhanced bactericidal activity. Nature Publishing Group UK 2020-10-15 /pmc/articles/PMC7562864/ /pubmed/33060695 http://dx.doi.org/10.1038/s41598-020-74401-5 Text en © The Author(s) 2020 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Sancho-Vaello, Enea Gil-Carton, David François, Patrice Bonetti, Eve-Julie Kreir, Mohamed Pothula, Karunakar Reddy Kleinekathöfer, Ulrich Zeth, Kornelius The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics |
title | The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics |
title_full | The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics |
title_fullStr | The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics |
title_full_unstemmed | The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics |
title_short | The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics |
title_sort | structure of the antimicrobial human cathelicidin ll-37 shows oligomerization and channel formation in the presence of membrane mimics |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562864/ https://www.ncbi.nlm.nih.gov/pubmed/33060695 http://dx.doi.org/10.1038/s41598-020-74401-5 |
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