Examinando por Autor "Dal Peraro, Matteo"
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Ítem Acceso Abierto A coiled coil switch mediates cold sensing by the thermosensory protein DesK(Wiley, 2015-10-08) Saita, Emilio Adolfo; Abriata, Luciano Andrés; Tsai, Yi-Ting; Trajtenberg, Felipe; Lemmin, Thomas; Buschiazzo, Alejandro; Dal Peraro, Matteo; De Mendoza, Diego; Albanesi, DanielaThe thermosensor histidine kinase DesK from Bacillus subtilis senses changes in membrane fluidity initiating an adaptive response. Structural changes in DesK have been implicated in transmembrane signaling, but direct evidence is still lacking. On the basis of structure-guided mutagenesis, we now propose a mechanism of DesK-mediated signal sensing and transduction. The data indicate that stabilization/destabilization of a 2-helix coiled coil, which connects the transmembrane sensory domain of DesK to its cytosolic catalytic region, is crucial to control its signaling state. Computational modeling and simulations reveal couplings between protein, water and membrane mechanics. We propose that membrane thickening is the main driving force for signal sensing and that it acts by inducing helix stretching and rotation prompting an asymmetric kinase-competent state. Overall, the known structural changes of the sensor kinase, as well as further dynamic rearrangements that we now predict, consistently link structure determinants to activity modulation.Ítem Acceso Abierto An experiment-informed signal transduction model for the role of the Staphylococcus aureus MecR1 protein in β-lactam resistance(Springer Nature, 2019-12-20) Belluzo, Bruno Salvador; Abriata, Luciano Andrés; Giannini, Estefanía; Mihovilcevic, Damila; Dal Peraro, Matteo; Llarrull, Leticia IreneThe 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.Ítem Acceso Abierto Transmembrane prolines mediate signal sensing and decoding in Bacillus subtilis DesK histidine kinase(American Society for Microbiology, 2019-11-26) Fernández, Pilar; Porrini, Lucía; Albanesi, Daniela; Abriata, Luciano Andrés; Dal Peraro, Matteo; De Mendoza, Diego; Mansilla, María Cecilia