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dc.contributor.authorAlbanesi, Daniela
dc.contributor.authorReh, Georgina
dc.contributor.authorGuerín, Marcelo Eduardo
dc.contributor.authorSchaeffer, Francis
dc.contributor.authorDebarbouille, Michel
dc.contributor.authorBuschiazzo, Alejandro
dc.contributor.authorSchujman, Gustavo E.
dc.contributor.authorDe Mendoza, Diego
dc.contributor.authorAlzari, Pedro M.
dc.date.accessioned2013-03-04T19:25:21Z
dc.date.available2013-03-04T19:25:21Z
dc.date.issued2013-01-03
dc.identifier.citationPLoS Pathog 9(1) : (2012) // e1003108es
dc.identifier.issn1553-7374
dc.identifier.urihttp://hdl.handle.net/10810/9588
dc.description11 p.es
dc.description.abstractThe biosynthesis of membrane lipids is an essential pathway for virtually all bacteria. Despite its potential importance for the development of novel antibiotics, little is known about the underlying signaling mechanisms that allow bacteria to control their membrane lipid composition within narrow limits. Recent studies disclosed an elaborate feed-forward system that senses the levels of malonyl-CoA and modulates the transcription of genes that mediate fatty acid and phospholipid synthesis in many Gram-positive bacteria including several human pathogens. A key component of this network is FapR, a transcriptional regulator that binds malonyl-CoA, but whose mode of action remains enigmatic. We report here the crystal structures of FapR from Staphylococcus aureus (SaFapR) in three relevant states of its regulation cycle. The repressor-DNA complex reveals that the operator binds two SaFapR homodimers with different affinities, involving sequence-specific contacts from the helix-turn-helix motifs to the major and minor grooves of DNA. In contrast with the elongated conformation observed for the DNA-bound FapR homodimer, binding of malonyl-CoA stabilizes a different, more compact, quaternary arrangement of the repressor, in which the two DNA-binding domains are attached to either side of the central thioesterase-like domain, resulting in a non-productive overall conformation that precludes DNA binding. The structural transition between the DNA-bound and malonyl-CoA-bound states of SaFapR involves substantial changes and large (>30 angstrom) inter-domain movements; however, both conformational states can be populated by the ligand-free repressor species, as confirmed by the structure of SaFapR in two distinct crystal forms. Disruption of the ability of SaFapR to monitor malonyl-CoA compromises cell growth, revealing the essentiality of membrane lipid homeostasis for S. aureus survival and uncovering novel opportunities for the development of antibiotics against this major human pathogen.es
dc.description.sponsorshipThis research was supported by grants from the Agence Nationale de la Recherche (ANR, France, contract ANR-06-PCVI-0009-01); Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina; Agencia de Promoción Científica y Tecnológica, Argentina; Institut Pasteur; CNRS (France) and ECOS France-Argentine (Action Grant A05B02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.es
dc.language.isoenges
dc.publisherPublic Library of Sciencees
dc.rightsinfo:eu-repo/semantics/openAccesses
dc.subjectfatty-acid synthesises
dc.subjectgram-positive pathogenses
dc.subjectantibacterial drug discoveryes
dc.subjectescherichia-colies
dc.subjectacyl-coenzymees
dc.subjectcrystal-structurees
dc.subjectfactor FapRes
dc.subjectpseudomonas-aeruginosaes
dc.subjectphospholipid-synthesises
dc.subjectbindinges
dc.titleStructural Basis for Feed-Forward Transcriptional Regulation of Membrane Lipid Homeostasis in Staphylococcus aureuses
dc.typeinfo:eu-repo/semantics/articlees
dc.rights.holder© 2013 Albanesi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.es
dc.relation.publisherversionhttp://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003108es
dc.identifier.doi10.1371/journal.ppat.1003108
dc.departamentoesBioquímica y biología moleculares_ES
dc.departamentoeuBiokimika eta biologia molekularraes_ES
dc.subject.categoriaGENETICS AND HEREDITY
dc.subject.categoriaVIROLOGY
dc.subject.categoriaPARASITOLOGY
dc.subject.categoriaMOLECULAR BIOLOGY
dc.subject.categoriaMICROBIOLOGY
dc.subject.categoriaIMMUNOLOGY AND MICROBIOLOGY


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