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dc.contributor.authorAmuategi Aulestiarte, Jone ORCID
dc.contributor.authorAlonso, Rocío
dc.contributor.authorOstolaza Echabe, Elena Amaya ORCID
dc.date.accessioned2022-08-12T08:11:53Z
dc.date.available2022-08-12T08:11:53Z
dc.date.issued2022
dc.identifier.citationInternational Journal of Molecular Sciences 23(15) : (2022) // Article ID 8703es_ES
dc.identifier.issn1422-0067
dc.identifier.urihttp://hdl.handle.net/10810/57299
dc.description.abstractAdenylate Cyclase Toxin (ACT or CyaA) is one of the important virulence factors secreted by Bordetella pertussis, the bacterium causative of whooping cough. ACT debilitates host defenses by production of unregulated levels of cAMP into the cell cytosol upon delivery of its N-terminal domain with adenylate cyclase activity (AC domain) and by forming pores in the plasma membrane of macrophages. Binding of soluble toxin monomers to the plasma membrane of target cells and conversion into membrane-integrated proteins are the first and last step for these toxin activities; however, the molecular determinants in the protein or the target membrane that govern this conversion to an active toxin form are fully unknown. It was previously reported that cytotoxic and cytolytic activities of ACT depend on membrane cholesterol. Here we show that ACT specifically interacts with membrane cholesterol, and find in two membrane-interacting ACT domains, four cholesterol-binding motifs that are essential for AC domain translocation and lytic activities. We hypothesize that direct ACT interaction with membrane cholesterol through those four cholesterol-binding motifs drives insertion and stabilizes the transmembrane topology of several helical elements that ultimately build the ACT structure for AC delivery and pore-formation, thereby explaining the cholesterol-dependence of the ACT activities. The requirement for lipid-mediated stabilization of transmembrane helices appears to be a unifying mechanism to modulate toxicity in pore-forming toxins.es_ES
dc.description.sponsorshipThis research was funded by the Spanish Ministerio de Economía y Competitividad [grant number BFU2017–82758-P] and by the Basque Government [grant number IT1264-19]. J.A. was recipient of a fellowship from the University of Basque Country (UPV/EHU). RA holds a contract funded by the Fundación Biofisika Bizkaia.es_ES
dc.language.isoenges_ES
dc.publisherMDPIes_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/es/
dc.subjectbacterial toxinses_ES
dc.subjectRTX toxinses_ES
dc.subjectpore-forming toxinses_ES
dc.subjectlipid-protein interactionses_ES
dc.titleFour Cholesterol-Recognition Motifs in the Pore-Forming and Translocation Domains of Adenylate Cyclase Toxin Are Essential for Invasion of Eukaryotic Cells and Lysis of Erythrocyteses_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.date.updated2022-08-11T11:50:57Z
dc.rights.holder© 2022 by the authors.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).es_ES
dc.relation.publisherversionhttps://www.mdpi.com/1422-0067/23/15/8703es_ES
dc.identifier.doihttps://doi.org/10.3390/ijms23158703
dc.departamentoesBioquímica y biología molecular
dc.departamentoeuBiokimika eta biologia molekularra


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© 2022 by the authors.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
Except where otherwise noted, this item's license is described as © 2022 by the authors.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).