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Mechanistic basis of choline import involved in teichoic acids and lipopolysaccharide modification
Phosphocholine molecules decorating bacterial cell wall teichoic acids and outer-membrane lipopolysaccharide have fundamental roles in adhesion to host cells, immune evasion, and persistence. Bacteria carrying the operon that performs phosphocholine decoration synthesize phosphocholine after uptake...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890701/ https://www.ncbi.nlm.nih.gov/pubmed/35235350 http://dx.doi.org/10.1126/sciadv.abm1122 |
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author | Bärland, Natalie Rueff, Anne-Stéphanie Cebrero, Gonzalo Hutter, Cedric A. J. Seeger, Markus A. Veening, Jan-Willem Perez, Camilo |
author_facet | Bärland, Natalie Rueff, Anne-Stéphanie Cebrero, Gonzalo Hutter, Cedric A. J. Seeger, Markus A. Veening, Jan-Willem Perez, Camilo |
author_sort | Bärland, Natalie |
collection | PubMed |
description | Phosphocholine molecules decorating bacterial cell wall teichoic acids and outer-membrane lipopolysaccharide have fundamental roles in adhesion to host cells, immune evasion, and persistence. Bacteria carrying the operon that performs phosphocholine decoration synthesize phosphocholine after uptake of the choline precursor by LicB, a conserved transporter among divergent species. Streptococcus pneumoniae is a prominent pathogen where phosphocholine decoration plays a fundamental role in virulence. Here, we present cryo–electron microscopy and crystal structures of S. pneumoniae LicB, revealing distinct conformational states and describing architectural and mechanistic elements essential to choline import. Together with in vitro and in vivo functional characterization, we found that LicB displays proton-coupled import activity and promiscuous selectivity involved in adaptation to choline deprivation conditions, and describe LicB inhibition by synthetic nanobodies (sybodies). Our results provide previously unknown insights into the molecular mechanism of a key transporter involved in bacterial pathogenesis and establish a basis for inhibition of the phosphocholine modification pathway across bacterial phyla. |
format | Online Article Text |
id | pubmed-8890701 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-88907012022-03-14 Mechanistic basis of choline import involved in teichoic acids and lipopolysaccharide modification Bärland, Natalie Rueff, Anne-Stéphanie Cebrero, Gonzalo Hutter, Cedric A. J. Seeger, Markus A. Veening, Jan-Willem Perez, Camilo Sci Adv Biomedicine and Life Sciences Phosphocholine molecules decorating bacterial cell wall teichoic acids and outer-membrane lipopolysaccharide have fundamental roles in adhesion to host cells, immune evasion, and persistence. Bacteria carrying the operon that performs phosphocholine decoration synthesize phosphocholine after uptake of the choline precursor by LicB, a conserved transporter among divergent species. Streptococcus pneumoniae is a prominent pathogen where phosphocholine decoration plays a fundamental role in virulence. Here, we present cryo–electron microscopy and crystal structures of S. pneumoniae LicB, revealing distinct conformational states and describing architectural and mechanistic elements essential to choline import. Together with in vitro and in vivo functional characterization, we found that LicB displays proton-coupled import activity and promiscuous selectivity involved in adaptation to choline deprivation conditions, and describe LicB inhibition by synthetic nanobodies (sybodies). Our results provide previously unknown insights into the molecular mechanism of a key transporter involved in bacterial pathogenesis and establish a basis for inhibition of the phosphocholine modification pathway across bacterial phyla. American Association for the Advancement of Science 2022-03-02 /pmc/articles/PMC8890701/ /pubmed/35235350 http://dx.doi.org/10.1126/sciadv.abm1122 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Bärland, Natalie Rueff, Anne-Stéphanie Cebrero, Gonzalo Hutter, Cedric A. J. Seeger, Markus A. Veening, Jan-Willem Perez, Camilo Mechanistic basis of choline import involved in teichoic acids and lipopolysaccharide modification |
title | Mechanistic basis of choline import involved in teichoic acids and lipopolysaccharide modification |
title_full | Mechanistic basis of choline import involved in teichoic acids and lipopolysaccharide modification |
title_fullStr | Mechanistic basis of choline import involved in teichoic acids and lipopolysaccharide modification |
title_full_unstemmed | Mechanistic basis of choline import involved in teichoic acids and lipopolysaccharide modification |
title_short | Mechanistic basis of choline import involved in teichoic acids and lipopolysaccharide modification |
title_sort | mechanistic basis of choline import involved in teichoic acids and lipopolysaccharide modification |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890701/ https://www.ncbi.nlm.nih.gov/pubmed/35235350 http://dx.doi.org/10.1126/sciadv.abm1122 |
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