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

doi:10.3390/antibiotics11050652

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Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1

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IAME, UMR 1137, INSERM, Université de Paris Cite, 75014 Paris, France

Service de Microbiologie, Hôpital Robert-Debré, AP-HP, 75019 Paris, France

UPMC, Institut de Calcul et de la Simulation, Sorbonne Universités, 75006 Paris, France

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Computational and Quantitative Biology, UPMC, UMR 7238, Sorbonne Universités, 75006 Paris, France

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Service de Bactériologie-Hygiène, Groupe Hospitalier Saint-Louis–Lariboisiére-Fernand Widal, AP-HP, 75010 Paris, France

Authors to whom correspondence should be addressed.

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These authors contributed equally to this work.

Academic Editor: Juan Ayala

Antibiotics 2022, 11(5), 652; https://doi.org/10.3390/antibiotics11050652

Received: 12 March 2022 / Revised: 29 April 2022 / Accepted: 5 May 2022 / Published: 13 May 2022

(This article belongs to the Special Issue How Far Are We from Predicting the Evolution of Antibiotic Resistance?)

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Abstract

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. View Full-Text

Keywords: entrenchment; protein stability; TEM-1 beta-lactamase; CTX-M-15 beta-lactamase; M182T mutation

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MDPI and ACS Style

Birgy, A.; Magnan, M.; Hobson, C.A.; Figliuzzi, M.; Panigoni, K.; Codde, C.; Tenaillon, O.; Jacquier, H. Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1. Antibiotics 2022, 11, 652. https://doi.org/10.3390/antibiotics11050652

AMA Style

Birgy A, Magnan M, Hobson CA, Figliuzzi M, Panigoni K, Codde C, Tenaillon O, Jacquier H. Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1. Antibiotics. 2022; 11(5):652. https://doi.org/10.3390/antibiotics11050652

Chicago/Turabian Style

Birgy, André, Mélanie Magnan, Claire A. Hobson, Matteo Figliuzzi, Karine Panigoni, Cyrielle Codde, Olivier Tenaillon, and Hervé Jacquier. 2022. "Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1" Antibiotics 11, no. 5: 652. https://doi.org/10.3390/antibiotics11050652

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Local and Global Protein Interactions Contribute to Residue Entrenchment in Beta-Lactamase TEM-1

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