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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
|
| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/11/5/652 |
| _version_ | 1797502075356053504 |
|---|---|
| author | André Birgy Mélanie Magnan Claire Amaris Hobson Matteo Figliuzzi Karine Panigoni Cyrielle Codde Olivier Tenaillon Hervé Jacquier |
| author_facet | André Birgy Mélanie Magnan Claire Amaris Hobson Matteo Figliuzzi Karine Panigoni Cyrielle Codde Olivier Tenaillon Hervé Jacquier |
| author_sort | André Birgy |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T03:27:41Z |
| format | Article |
| id | doaj.art-ccabf411f744474dbc7ac7f7096993d5 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T03:27:41Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-ccabf411f744474dbc7ac7f7096993d52023-11-23T09:49:11ZengMDPI AGAntibiotics2079-63822022-05-0111565210.3390/antibiotics11050652Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1André Birgy0Mélanie Magnan1Claire Amaris Hobson2Matteo Figliuzzi3Karine Panigoni4Cyrielle Codde5Olivier Tenaillon6Hervé Jacquier7IAME, UMR 1137, INSERM, Université de Paris Cite, 75014 Paris, FranceIAME, UMR 1137, INSERM, Université de Paris Cite, 75014 Paris, FranceIAME, UMR 1137, INSERM, Université de Paris Cite, 75014 Paris, FranceUPMC, Institut de Calcul et de la Simulation, Sorbonne Universités, 75006 Paris, FranceIAME, UMR 1137, INSERM, Université de Paris Cite, 75014 Paris, FranceIAME, UMR 1137, INSERM, Université de Paris Cite, 75014 Paris, FranceIAME, UMR 1137, INSERM, Université de Paris Cite, 75014 Paris, FranceIAME, UMR 1137, INSERM, Université de Paris Cite, 75014 Paris, FranceDue 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.https://www.mdpi.com/2079-6382/11/5/652entrenchmentprotein stabilityTEM-1 beta-lactamaseCTX-M-15 beta-lactamaseM182T mutation |
| spellingShingle | André Birgy Mélanie Magnan Claire Amaris Hobson Matteo Figliuzzi Karine Panigoni Cyrielle Codde Olivier Tenaillon Hervé Jacquier Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1 Antibiotics entrenchment protein stability TEM-1 beta-lactamase CTX-M-15 beta-lactamase M182T mutation |
| 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 | entrenchment protein stability TEM-1 beta-lactamase CTX-M-15 beta-lactamase M182T mutation |
| url | https://www.mdpi.com/2079-6382/11/5/652 |
| work_keys_str_mv | AT andrebirgy localandglobalproteininteractionscontributetoresidueentrenchmentinbetalactamasetem1 AT melaniemagnan localandglobalproteininteractionscontributetoresidueentrenchmentinbetalactamasetem1 AT claireamarishobson localandglobalproteininteractionscontributetoresidueentrenchmentinbetalactamasetem1 AT matteofigliuzzi localandglobalproteininteractionscontributetoresidueentrenchmentinbetalactamasetem1 AT karinepanigoni localandglobalproteininteractionscontributetoresidueentrenchmentinbetalactamasetem1 AT cyriellecodde localandglobalproteininteractionscontributetoresidueentrenchmentinbetalactamasetem1 AT oliviertenaillon localandglobalproteininteractionscontributetoresidueentrenchmentinbetalactamasetem1 AT hervejacquier localandglobalproteininteractionscontributetoresidueentrenchmentinbetalactamasetem1 |