Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus

Autores
Albanesi, Daniela; Reh, Georgina; Guerin, Marcelo E.; Schaeffer, Francis; Debarbouille, Michel; Buschiazzo, Alejandro; Schujman, Gustavo Enrique; de Mendoza, Diego; Alzari, Pedro
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The 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 Å) 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.
Fil: Albanesi, Daniela. Institut Pasteur. Unité de Microbiologie Structurale; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Reh, Georgina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Guerin, Marcelo E.. Centro Mixto CSIC-UPV/EHU. Unidad de Biofisica; España. Universidad del Pais Vasco; España. Basque Foundation for Science. IKERBASQUE; España
Fil: Schaeffer, Francis. Institut Pasteur. Unité de Microbiologie Structurale; Francia
Fil: Debarbouille, Michel. Institut Pasteur. Unité de Biologie des Bactéries Pathogènes è Gram Positif; Francia
Fil: Buschiazzo, Alejandro. Institut Pasteur. Unité de Microbiologie Structurale; Francia
Fil: Schujman, Gustavo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: de Mendoza, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Alzari, Pedro. Institut Pasteur. Unité de Microbiologie Structurale; Francia
Materia
Lipid Homeostasis
Transcriptional Regulation
Staphylococcus aureus
Antibiotic target
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/4840
Acceder
id CONICETDig_4b5b0f9211a6167b6925883239ebd242
oai_identifier_str oai:ri.conicet.gov.ar:11336/4840
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureusAlbanesi, DanielaReh, GeorginaGuerin, Marcelo E.Schaeffer, FrancisDebarbouille, MichelBuschiazzo, AlejandroSchujman, Gustavo Enriquede Mendoza, DiegoAlzari, PedroLipid HomeostasisTranscriptional RegulationStaphylococcus aureusAntibiotic targethttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The 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 Å) 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.Fil: Albanesi, Daniela. Institut Pasteur. Unité de Microbiologie Structurale; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Reh, Georgina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Guerin, Marcelo E.. Centro Mixto CSIC-UPV/EHU. Unidad de Biofisica; España. Universidad del Pais Vasco; España. Basque Foundation for Science. IKERBASQUE; EspañaFil: Schaeffer, Francis. Institut Pasteur. Unité de Microbiologie Structurale; FranciaFil: Debarbouille, Michel. Institut Pasteur. Unité de Biologie des Bactéries Pathogènes è Gram Positif; FranciaFil: Buschiazzo, Alejandro. Institut Pasteur. Unité de Microbiologie Structurale; FranciaFil: Schujman, Gustavo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: de Mendoza, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Alzari, Pedro. Institut Pasteur. Unité de Microbiologie Structurale; FranciaPublic Library Of Science2013-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4840Albanesi, Daniela; Reh, Georgina; Guerin, Marcelo E.; Schaeffer, Francis; Debarbouille, Michel; et al.; Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus; Public Library Of Science; Plos Pathogens; 9; 1; 1-2013; e1003108-e10031081553-7366enginfo:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003108info:eu-repo/semantics/altIdentifier/doi/10.1371%2Fjournal.ppat.1003108info:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/altIdentifier/pmid/PMC3536700info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536700/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:16:59Zoai:ri.conicet.gov.ar:11336/4840instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:16:59.287CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus
title Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus
spellingShingle Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus
Albanesi, Daniela
Lipid Homeostasis
Transcriptional Regulation
Staphylococcus aureus
Antibiotic target
title_short Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus
title_full Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus
title_fullStr Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus
title_full_unstemmed Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus
title_sort Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus
dc.creator.none.fl_str_mv Albanesi, Daniela
Reh, Georgina
Guerin, Marcelo E.
Schaeffer, Francis
Debarbouille, Michel
Buschiazzo, Alejandro
Schujman, Gustavo Enrique
de Mendoza, Diego
Alzari, Pedro
author Albanesi, Daniela
author_facet Albanesi, Daniela
Reh, Georgina
Guerin, Marcelo E.
Schaeffer, Francis
Debarbouille, Michel
Buschiazzo, Alejandro
Schujman, Gustavo Enrique
de Mendoza, Diego
Alzari, Pedro
author_role author
author2 Reh, Georgina
Guerin, Marcelo E.
Schaeffer, Francis
Debarbouille, Michel
Buschiazzo, Alejandro
Schujman, Gustavo Enrique
de Mendoza, Diego
Alzari, Pedro
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Lipid Homeostasis
Transcriptional Regulation
Staphylococcus aureus
Antibiotic target
topic Lipid Homeostasis
Transcriptional Regulation
Staphylococcus aureus
Antibiotic target
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The 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 Å) 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.
Fil: Albanesi, Daniela. Institut Pasteur. Unité de Microbiologie Structurale; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Reh, Georgina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Guerin, Marcelo E.. Centro Mixto CSIC-UPV/EHU. Unidad de Biofisica; España. Universidad del Pais Vasco; España. Basque Foundation for Science. IKERBASQUE; España
Fil: Schaeffer, Francis. Institut Pasteur. Unité de Microbiologie Structurale; Francia
Fil: Debarbouille, Michel. Institut Pasteur. Unité de Biologie des Bactéries Pathogènes è Gram Positif; Francia
Fil: Buschiazzo, Alejandro. Institut Pasteur. Unité de Microbiologie Structurale; Francia
Fil: Schujman, Gustavo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: de Mendoza, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Alzari, Pedro. Institut Pasteur. Unité de Microbiologie Structurale; Francia
description The 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 Å) 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.
publishDate 2013
dc.date.none.fl_str_mv 2013-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/4840
Albanesi, Daniela; Reh, Georgina; Guerin, Marcelo E.; Schaeffer, Francis; Debarbouille, Michel; et al.; Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus; Public Library Of Science; Plos Pathogens; 9; 1; 1-2013; e1003108-e1003108
1553-7366
url http://hdl.handle.net/11336/4840
identifier_str_mv Albanesi, Daniela; Reh, Georgina; Guerin, Marcelo E.; Schaeffer, Francis; Debarbouille, Michel; et al.; Structural basis for feed-forward transcriptional regulation of membrane lipid homeostasis in Staphylococcus aureus; Public Library Of Science; Plos Pathogens; 9; 1; 1-2013; e1003108-e1003108
1553-7366
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003108
info:eu-repo/semantics/altIdentifier/doi/10.1371%2Fjournal.ppat.1003108
info:eu-repo/semantics/altIdentifier/doi/
info:eu-repo/semantics/altIdentifier/pmid/PMC3536700
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536700/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library Of Science
publisher.none.fl_str_mv Public Library Of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842980927665340416
score 12.993085

Publicaciones similares