An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4.
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.
Motshwene
Precious G
PG
Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
Moncrieffe
Martin C
MC
Grossmann
J Günter
JG
Kao
Cheng
C
Ayaluru
Murali
M
Sandercock
Alan M
AM
Robinson
Carol V
CV
Latz
Eicke
E
Gay
Nicholas J
NJ
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
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