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An experiment-informed signal transduction model for the role of the Staphylococcus aureus MecR1 protein in β-lactam resistance

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dc.citation.titleScientific Reports
dc.citation.volume9
dc.creatorBelluzo, Bruno Salvador
dc.creatorAbriata, Luciano Andrés
dc.creatorGiannini, Estefanía
dc.creatorMihovilcevic, Damila
dc.creatorDal Peraro, Matteo
dc.creatorLlarrull, Leticia Irene
dc.date.accessioned2024-05-31T19:24:36Z
dc.date.available2024-05-31T19:24:36Z
dc.date.issued2019-12-20
dc.description.abstractThe treatment of hospital- and community-associated infections by methicillin-resistant Staphylococcus aureus (MRSA) is a perpetual challenge. This Gram-positive bacterium is resistant specifically to β-lactam antibiotics, and generally to many other antibacterial agents. Its resistance mechanisms to β-lactam antibiotics are activated only when the bacterium encounters a β-lactam. This activation is regulated by the transmembrane sensor/signal transducer proteins BlaR1 and MecR1. Neither the transmembrane/metalloprotease domain, nor the complete MecR1 and BlaR1 proteins, are isolatable for mechanistic study. Here we propose a model for full-length MecR1 based on homology modeling, residue coevolution data, a new extensive experimental mapping of transmembrane topology, partial structures, molecular simulations, and available NMR data. Our model defines the metalloprotease domain as a hydrophilic transmembrane chamber effectively sealed by the apo-sensor domain. It proposes that the amphipathic helices inserted into the gluzincin domain constitute the route for transmission of the β-lactam-binding event in the extracellular sensor domain, to the intracellular and membrane-embedded zinc-containing active site. From here, we discuss possible routes for subsequent activation of proteolytic action. This study provides the first coherent model of the structure of MecR1, opening routes for future functional investigations on how β-lactam binding culminates in the proteolytic degradation of MecI.
dc.description.filFil: Belluzo, Bruno Salvador. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Giannini, Estefanía. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Mihovilcevic, Damila. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Llarrull, Leticia Irene. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Llarrull, Leticia Irene. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Biofísica; Argentina.
dc.description.filFil: Abriata, Luciano Andrés. École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics. Laboratory for Biomolecular Modeling; Switzerland.
dc.description.filFil: Dal Peraro, Matteo. École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics. Laboratory for Biomolecular Modeling; Switzerland.
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
dc.description.sponsorshipAgencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación (Agencia I+D+i): PICT 2011-0949, PICT 2015-2521
dc.description.sponsorshipThe Pew Charitable Trusts. The Pew Latin American Fellows Program in the Biomedical Sciences
dc.description.versionpeerreviewed
dc.format.extent1-15
dc.identifier.issn2045-2322
dc.identifier.urihttps://hdl.handle.net/2133/27119
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.publisherversionhttps://doi.org/10.1038/s41598-019-55923-z
dc.relation.publisherversionhttps://www.nature.com/articles/s41598-019-55923-z
dc.rightsopenAccess
dc.rights.holderBelluzo, Bruno Salvador
dc.rights.holderAbriata, Luciano Andrés
dc.rights.holderGiannini, Estefanía
dc.rights.holderMihovilcevic, Damila
dc.rights.holderDal Peraro, Matteo
dc.rights.holderLlarrull, Leticia Irene
dc.rights.holderUniversidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas
dc.rights.textAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectStaphylococcus aureus
dc.subjectSignal transduction
dc.subjectMecR1 protein
dc.subjectMethicillin resistance
dc.subjectMethicillin-resistant Staphylococcus aureus
dc.subjectDrug resistance, bacterial
dc.subjectBeta-lactam resistance
dc.subjectHealthcare-associated infections
dc.subjectCross infection
dc.titleAn experiment-informed signal transduction model for the role of the Staphylococcus aureus MecR1 protein in β-lactam resistance
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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