Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 13 March 2022 / Approved: 17 March 2022 / Online: 17 March 2022 (08:43:11 CET)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Antibiotics 2022, 11, 652
DOI: 10.3390/antibiotics11050652

Abstract

Abstract: Due to their rapid evolution and their impact on health care, be-ta-lactamases, protein degrading beta-lactam antibiotics, are used as generic model 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 is in-activating the protein’s function just as the reciprocal mutation W251G in CTXM-15. Phylogenetic analysis revealed that mutation G has been entrenched in TEM-1 background: while rarely observed throughout the phylogeny it is es-sential in TEM-1. Using a rescue experiment in TEM-1 G251W mutant, we could identify sites that alleviates the deviation from G to W. While few of these muta-tions could potentially involve local interactions, most of them were found on distant residues in the 3D structure. Many well-known mutations having an impact on protein stability, such as M182T, were recovered. Our results there-fore suggest that entrenchment of an amino acid may rely on diffuse interactions among multiple sites with a major impact on protein stability.

Keywords

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

Subject

LIFE SCIENCES, Genetics

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