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dc.contributor.authorO'NEILL, LUKE ANTHONY JOHNen
dc.contributor.authorDUNNE, AISLINGen
dc.date.accessioned2009-09-30T21:55:04Z
dc.date.available2009-09-30T21:55:04Z
dc.date.issued2003en
dc.date.submitted2003en
dc.identifier.citationA. Dunne, M. Ejdeback, P. L. Ludidi, L. A. O'Neill and N. J. Gay, Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88, The Journal of Biological Chemistry, 278, 42, 2003, 41443-41451en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/33692
dc.descriptionPUBLISHEDen
dc.descriptionPMID: 12888566en
dc.description.abstractThe Toll/interleukin 1 receptor (TIR) domain is a region found in the cytoplasmic tails of members of the Toll-like receptor/interleukin-1 receptor superfamily. The domain is essential for signaling and is also found in the adaptor proteins Mal (MyD88 adaptor-like) and MyD88, which function to couple activation of the receptor to downstream signaling components. Experimental structures of two Toll/interleukin 1 receptor domains reveal a ???-fold similar to that of the bacterial chemotaxis protein CheY, and other evidence suggests that the adaptors can make heterotypic interactions with both the receptors and themselves. Here we show that the purified TIR domains of Mal and MyD88 can form stable heterodimers and also that Mal homodimers and oligomers are dissociated in the presence of ATP. To identify structural features that may contribute to the formation of signaling complexes, we produced models of the TIR domains from human Toll-like receptor 4 (TLR4), Mal, and MyD88. We found that although the overall fold is conserved the electrostatic surface potentials are quite distinct. Docking studies of the models suggest that Mal and MyD88 bind to different regions in TLRs 2 and 4, a finding consistent with a cooperative role of the two adaptors in signaling. Mal and MyD88 are predicted to interact at a third non-overlapping site, suggesting that the receptor and adaptors may form heterotetrameric complexes. The theoretical model of the interactions is supported by experimental data from glutathione S-transferase pull-downs and co-immunoprecipitations. Neither theoretical nor experimental data suggest a direct role for the conserved proline in the BB-loop in the association of TLR4, Mal, and MyD88. Finally we show a sequence relationship between the Drosophila protein Tube and Mal that may indicate a functional equivalence of these two adaptors in the Drosophila and vertebrate Toll pathways.en
dc.description.sponsorshipWe thank the Science Foundation Ireland, Amgen Inc., and the UK Biotechnology and Biological Sciences Research Council.en
dc.format.extent41443-41451en
dc.format.mimetypeapplication/pdf
dc.language.isoenen
dc.relation.ispartofseriesThe Journal of Biological Chemistryen
dc.relation.ispartofseries278en
dc.relation.ispartofseries42en
dc.rightsYen
dc.subjectBiochemistryen
dc.titleStructural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88en
dc.typeJournal Articleen
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/laoneillen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/aidunneen
dc.identifier.rssinternalid20830en
dc.identifier.rssuri10.1074/jbc.M301742200


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