Cargando…
Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae
Multidrug and toxic compound extrusion (MATE) transport proteins confer multidrug resistance on pathogenic microorganisms and affect pharmacokinetics in mammals. Our understanding of how MATE transporters work, has mostly relied on protein structures and MD simulations. However, the energetics of dr...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113278/ https://www.ncbi.nlm.nih.gov/pubmed/33976372 http://dx.doi.org/10.1038/s42003-021-02081-6 |
_version_ | 1783690827349884928 |
---|---|
author | Raturi, Sagar Nair, Asha V. Shinoda, Keiko Singh, Himansha Bai, Boyan Murakami, Satoshi Fujitani, Hideaki van Veen, Hendrik W. |
author_facet | Raturi, Sagar Nair, Asha V. Shinoda, Keiko Singh, Himansha Bai, Boyan Murakami, Satoshi Fujitani, Hideaki van Veen, Hendrik W. |
author_sort | Raturi, Sagar |
collection | PubMed |
description | Multidrug and toxic compound extrusion (MATE) transport proteins confer multidrug resistance on pathogenic microorganisms and affect pharmacokinetics in mammals. Our understanding of how MATE transporters work, has mostly relied on protein structures and MD simulations. However, the energetics of drug transport has not been studied in detail. Many MATE transporters utilise the electrochemical H(+) or Na(+) gradient to drive substrate efflux, but NorM-VC from Vibrio cholerae can utilise both forms of metabolic energy. To dissect the localisation and organisation of H(+) and Na(+) translocation pathways in NorM-VC we engineered chimaeric proteins in which the N-lobe of H(+)-coupled NorM-PS from Pseudomonas stutzeri is fused to the C-lobe of NorM-VC, and vice versa. Our findings in drug binding and transport experiments with chimaeric, mutant and wildtype transporters highlight the versatile nature of energy coupling in NorM-VC, which enables adaptation to fluctuating salinity levels in the natural habitat of V. cholerae. |
format | Online Article Text |
id | pubmed-8113278 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81132782021-05-12 Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae Raturi, Sagar Nair, Asha V. Shinoda, Keiko Singh, Himansha Bai, Boyan Murakami, Satoshi Fujitani, Hideaki van Veen, Hendrik W. Commun Biol Article Multidrug and toxic compound extrusion (MATE) transport proteins confer multidrug resistance on pathogenic microorganisms and affect pharmacokinetics in mammals. Our understanding of how MATE transporters work, has mostly relied on protein structures and MD simulations. However, the energetics of drug transport has not been studied in detail. Many MATE transporters utilise the electrochemical H(+) or Na(+) gradient to drive substrate efflux, but NorM-VC from Vibrio cholerae can utilise both forms of metabolic energy. To dissect the localisation and organisation of H(+) and Na(+) translocation pathways in NorM-VC we engineered chimaeric proteins in which the N-lobe of H(+)-coupled NorM-PS from Pseudomonas stutzeri is fused to the C-lobe of NorM-VC, and vice versa. Our findings in drug binding and transport experiments with chimaeric, mutant and wildtype transporters highlight the versatile nature of energy coupling in NorM-VC, which enables adaptation to fluctuating salinity levels in the natural habitat of V. cholerae. Nature Publishing Group UK 2021-05-11 /pmc/articles/PMC8113278/ /pubmed/33976372 http://dx.doi.org/10.1038/s42003-021-02081-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Raturi, Sagar Nair, Asha V. Shinoda, Keiko Singh, Himansha Bai, Boyan Murakami, Satoshi Fujitani, Hideaki van Veen, Hendrik W. Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae |
title | Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae |
title_full | Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae |
title_fullStr | Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae |
title_full_unstemmed | Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae |
title_short | Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae |
title_sort | engineered mate multidrug transporters reveal two functionally distinct ion-coupling pathways in norm from vibrio cholerae |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113278/ https://www.ncbi.nlm.nih.gov/pubmed/33976372 http://dx.doi.org/10.1038/s42003-021-02081-6 |
work_keys_str_mv | AT raturisagar engineeredmatemultidrugtransportersrevealtwofunctionallydistinctioncouplingpathwaysinnormfromvibriocholerae AT nairashav engineeredmatemultidrugtransportersrevealtwofunctionallydistinctioncouplingpathwaysinnormfromvibriocholerae AT shinodakeiko engineeredmatemultidrugtransportersrevealtwofunctionallydistinctioncouplingpathwaysinnormfromvibriocholerae AT singhhimansha engineeredmatemultidrugtransportersrevealtwofunctionallydistinctioncouplingpathwaysinnormfromvibriocholerae AT baiboyan engineeredmatemultidrugtransportersrevealtwofunctionallydistinctioncouplingpathwaysinnormfromvibriocholerae AT murakamisatoshi engineeredmatemultidrugtransportersrevealtwofunctionallydistinctioncouplingpathwaysinnormfromvibriocholerae AT fujitanihideaki engineeredmatemultidrugtransportersrevealtwofunctionallydistinctioncouplingpathwaysinnormfromvibriocholerae AT vanveenhendrikw engineeredmatemultidrugtransportersrevealtwofunctionallydistinctioncouplingpathwaysinnormfromvibriocholerae |