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Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1
Due to their rapid evolution and their impact on healthcare, beta-lactamases, protein degrading beta-lactam antibiotics, are used as generic models of protein evolution. Therefore, we investigated the mutation effects in two distant beta-lactamases, TEM-1 and CTX-M-15. Interestingly, we found a site...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137480/ https://www.ncbi.nlm.nih.gov/pubmed/35625296 http://dx.doi.org/10.3390/antibiotics11050652 |
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author | Birgy, André Magnan, Mélanie Hobson, Claire Amaris Figliuzzi, Matteo Panigoni, Karine Codde, Cyrielle Tenaillon, Olivier Jacquier, Hervé |
author_facet | Birgy, André Magnan, Mélanie Hobson, Claire Amaris Figliuzzi, Matteo Panigoni, Karine Codde, Cyrielle Tenaillon, Olivier Jacquier, Hervé |
author_sort | Birgy, André |
collection | PubMed |
description | Due to their rapid evolution and their impact on healthcare, beta-lactamases, protein degrading beta-lactam antibiotics, are used as generic models of protein evolution. Therefore, we investigated the mutation effects in two distant beta-lactamases, TEM-1 and CTX-M-15. Interestingly, we found a site with a complex pattern of genetic interactions. Mutation G251W in TEM-1 inactivates the protein’s function, just as the reciprocal mutation, W251G, does in CTX-M-15. The phylogenetic analysis revealed that mutation G has been entrenched in TEM-1’s background: while rarely observed throughout the phylogeny, it is essential in TEM-1. Using a rescue experiment, in the TEM-1 G251W mutant, we identified sites that alleviate the deviation from G to W. While few of these mutations could potentially involve local interactions, most of them were found on distant residues in the 3D structure. Many well-known mutations that have an impact on protein stability, such as M182T, were recovered. Our results therefore suggest that entrenchment of an amino acid may rely on diffuse interactions among multiple sites, with a major impact on protein stability. |
format | Online Article Text |
id | pubmed-9137480 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91374802022-05-28 Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1 Birgy, André Magnan, Mélanie Hobson, Claire Amaris Figliuzzi, Matteo Panigoni, Karine Codde, Cyrielle Tenaillon, Olivier Jacquier, Hervé Antibiotics (Basel) Article Due to their rapid evolution and their impact on healthcare, beta-lactamases, protein degrading beta-lactam antibiotics, are used as generic models of protein evolution. Therefore, we investigated the mutation effects in two distant beta-lactamases, TEM-1 and CTX-M-15. Interestingly, we found a site with a complex pattern of genetic interactions. Mutation G251W in TEM-1 inactivates the protein’s function, just as the reciprocal mutation, W251G, does in CTX-M-15. The phylogenetic analysis revealed that mutation G has been entrenched in TEM-1’s background: while rarely observed throughout the phylogeny, it is essential in TEM-1. Using a rescue experiment, in the TEM-1 G251W mutant, we identified sites that alleviate the deviation from G to W. While few of these mutations could potentially involve local interactions, most of them were found on distant residues in the 3D structure. Many well-known mutations that have an impact on protein stability, such as M182T, were recovered. Our results therefore suggest that entrenchment of an amino acid may rely on diffuse interactions among multiple sites, with a major impact on protein stability. MDPI 2022-05-13 /pmc/articles/PMC9137480/ /pubmed/35625296 http://dx.doi.org/10.3390/antibiotics11050652 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Birgy, André Magnan, Mélanie Hobson, Claire Amaris Figliuzzi, Matteo Panigoni, Karine Codde, Cyrielle Tenaillon, Olivier Jacquier, Hervé Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1 |
title | Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1 |
title_full | Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1 |
title_fullStr | Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1 |
title_full_unstemmed | Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1 |
title_short | Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1 |
title_sort | local and global protein interactions contribute to residue entrenchment in beta-lactamase tem-1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137480/ https://www.ncbi.nlm.nih.gov/pubmed/35625296 http://dx.doi.org/10.3390/antibiotics11050652 |
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