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Slow protein dynamics elicits new enzymatic functions by means of epistatic interactions

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dc.citation.titleMolecular Biology and Evolution
dc.citation.volume39
dc.contributor.orcidhttps://orcid.org/0000-0002-7978-3233
dc.creatorRossi, María Agustina
dc.creatorPalzkill, Timothy
dc.creatorAlmeida, Fabio C. L.
dc.creatorVila, Alejandro J.
dc.date.accessioned2024-10-28T15:29:07Z
dc.date.available2024-10-28T15:29:07Z
dc.date.issued2022-09-22
dc.description.abstractProtein evolution depends on the adaptation of these molecules to different functional challenges. This occurs by tuning their biochemical, biophysical, and structural traits through the accumulation of mutations. While the role of protein dynamics in biochemistry is well recognized, there are limited examples providing experimental evidence of the optimization of protein dynamics during evolution. Here we report an NMR study of four variants of the CTX-M β-lactamases, in which the interplay of two mutations outside the active site enhances the activity against a cephalosporin substrate, ceftazidime. The crystal structures of these enzymes do not account for this activity enhancement. By using NMR, here we show that the combination of these two mutations increases the backbone dynamics in a slow timescale and the exposure to the solvent of an otherwise buried β-sheet. The two mutations located in this β-sheet trigger conformational changes in loops located at the opposite side of the active site. We postulate that the most active variant explores alternative conformations that enable binding of the more challenging substrate ceftazidime. The impact of the mutations in the dynamics is context-dependent, in line with the epistatic effect observed in the catalytic activity of the different variants. These results reveal the existence of a dynamic network in CTX-M β-lactamases that has been exploited in evolution to provide a net gain-of-function, highlighting the role of alternative conformations in protein evolution.
dc.description.filFil: Rossi, María Agustina. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Palzkill, Timothy. Baylor College of Medicine. Department of Pharmacology and Chemical Biology; USA.
dc.description.filFil: Palzkill, Timothy. Baylor College of Medicine- Verna and Marrs McLean Department of Biochemistry and Molecular Biology; USA.
dc.description.filFil: Almeida, Fabio C. L. Federal University of Rio de Janeiro. National Center for Structural Biology and Bioimaging. Institute of Medical Biochemistry Leopoldo de Meis (IBqM9); Brazil.
dc.description.filFil: Vila, Alejandro J. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.
dc.description.sponsorshipNational Institute of Allergy and Infectious Diseases (NIAID): 2R01AI100560-06A1
dc.description.sponsorshipFondo para la Investigación Científica y Tecnológica (FONCYT): PICT-2016-1657
dc.description.sponsorshipFundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ): NIH AI32956, 255.940/2020, 239.229/2018, 210.361/2015, 204.432/2014
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq): 309564/2017
dc.format.extent1-12
dc.identifier.citationMaria-Agustina Rossi, Timothy Palzkill, Fabio C L Almeida, Alejandro J Vila, Slow Protein Dynamics Elicits New Enzymatic Functions by Means of Epistatic Interactions, Molecular Biology and Evolution, Volume 39, Issue 10, October 2022, msac194, https://doi.org/10.1093/molbev/msac194
dc.identifier.issn1537-1719
dc.identifier.urihttps://hdl.handle.net/2133/27990
dc.language.isoen
dc.publisherOxford University Press
dc.relation.publisherversionhttps://doi.org/10.1093/molbev/msac194
dc.relation.publisherversionhttps://academic.oup.com/mbe/article/39/10/msac194/6711538?login=true
dc.rightsopenAccess
dc.rights.holderRossi, María Agustina
dc.rights.holderPalzkill, Timothy
dc.rights.holderAlmeida, Fabio C. L.
dc.rights.holderVila, Alejandro J.
dc.rights.textAttribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectProtein evolution
dc.subjectEpistasis
dc.subjectβ-lactamase
dc.subjectAlternative conformations
dc.titleSlow protein dynamics elicits new enzymatic functions by means of epistatic interactions
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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