A dimer of the toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins

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dc.contributor.authorMiguel, Ricardo Nunezen_ZA
dc.contributor.authorWong, Joyceen_ZA
dc.contributor.authorWestoll, Julian F.en_ZA
dc.contributor.authorBrooks, Heather J.en_ZA
dc.contributor.authorO'Neill, Luke A. J.en_ZA
dc.contributor.authorGay, Nicholas J.en_ZA
dc.contributor.authorBryant, Clare E.en_ZA
dc.contributor.authorMonie, Tom P.en_ZA
dc.date.accessioned2011-05-15T16:00:17Z
dc.date.available2011-05-15T16:00:17Z
dc.date.issued2007-08-29
dc.descriptionCITATION: Miguel, R. N. et al. 2007. A dimer of the toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins. PLoS ONE, 2(8): e788, doi:10.1371/journal.pone.0000788.
dc.descriptionThe original publication is available at http://journals.plos.org/plosone
dc.description.abstractThe Toll-like receptor 4 (TLR4) is a class I transmembrane receptor expressed on the surface of immune system cells. TLR4 is activated by exposure to lipopolysaccharides derived from the outer membrane of Gram negative bacteria and forms part of the innate immune response in mammals. Like other class 1 receptors, TLR4 is activated by ligand induced dimerization, and recent studies suggest that this causes concerted conformational changes in the receptor leading to self association of the cytoplasmic Toll/Interleukin 1 receptor (TIR) signalling domain. This homodimerization event is proposed to provide a new scaffold that is able to bind downstream signalling adaptor proteins. TLR4 uses two different sets of adaptors; TRAM and TRIF, and Mal and MyD88. These adaptor pairs couple two distinct signalling pathways leading to the activation of interferon response factor 3 (IRF-3) and nuclear factor κB (NFκB) respectively. In this paper we have generated a structural model of the TLR4 TIR dimer and used molecular docking to probe for potential sites of interaction between the receptor homodimer and the adaptor molecules. Remarkably, both the Mal and TRAM adaptors are strongly predicted to bind at two symmetry-related sites at the homodimer interface. This model of TLR4 activation is supported by extensive functional studies involving site directed mutagenesis, inhibition by cell permeable peptides and stable protein phosphorylation of receptor and adaptor TIR domains. Our results also suggest a molecular mechanism for two recent findings, the caspase 1 dependence of Mal signalling and the protective effects conferred by the Mal polymorphism Ser180Leu. © 2007 Núñez Miguel et al.
dc.description.urihttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0000788
dc.description.versionPublisher's version
dc.format.extent12 pages
dc.identifier.citationMiguel, R. N. et al. 2007. A dimer of the toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins. PLoS ONE, 2(8): e788, doi:10.1371/journal.pone.0000788.
dc.identifier.issn1932-6203 (online)
dc.identifier.otherdoi:10.1371/journal.pone.0000788
dc.identifier.urihttp://hdl.handle.net/10019.1/11620
dc.language.isoen
dc.publisherPublic Library of Science
dc.rights.holderAuthors retain copyright
dc.subjectImmune systemen_ZA
dc.subjectReceptors, Cellen_ZA
dc.subjectProteinsen_ZA
dc.titleA dimer of the toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteinsen_ZA
dc.typeArticle
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