title: An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4.
abstract: Toll-like receptors (TLRs) mediate responses to pathogen-associated molecules as part of the vertebrate innate immune response to infection. Receptor dimerization is coupled to downstream signal transduction by the recruitment of a post-receptor complex containing the adaptor protein MyD88 and the IRAK protein kinases. In this work, we show that the death domains of human MyD88 and IRAK-4 assemble into closed complexes having unusual stoichiometries of 7:4 and 8:4, the Myddosome. Formation of the Myddosome is likely to be a key event for TLR4 signaling in vivo as we show here that pathway activation requires that the receptors cluster into lipid rafts. Taken together, these findings indicate that TLR activation causes the formation of a highly oligomeric signaling platform analogous to the death-inducing signaling complex of the Fas receptor pathway.
authors: Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
authors: Precious G
authors: PG
authors: Motshwene
authors: Martin C
authors: MC
authors: Moncrieffe
authors: J Günter
authors: JG
authors: Grossmann
authors: Cheng
authors: C
authors: Kao
authors: Murali
authors: M
authors: Ayaluru
authors: Alan M
authors: AM
authors: Sandercock
authors: Carol V
authors: CV
authors: Robinson
authors: Eicke
authors: E
authors: Latz
authors: Nicholas J
authors: NJ
authors: Gay
mesh_terms: D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000737:chemistry*; D013058:Mass Spectrometry / Q000379:methods; D021962:Membrane Microdomains / Q000737:chemistry; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D012542:Scattering, Radiation; D015398:Signal Transduction; D014461:Ultracentrifugation; D014965:X-Rays; D019014:fas Receptor / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D019014:fas Receptor; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases