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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...

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Autores principales: Birgy, André, Magnan, Mélanie, Hobson, Claire Amaris, Figliuzzi, Matteo, Panigoni, Karine, Codde, Cyrielle, Tenaillon, Olivier, Jacquier, Hervé
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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