The death domain of IRAK-1: an oligomerization domain mediating interactions with MyD88, Tollip, IRAK-1, and IRAK-4.
Ligand binding in the Toll-like/interleukin-1 receptor family results in the recruitment of an intracellular signaling complex. IRAK-1, which is centrally involved in this complex, is able to homo-oligomerize and to bind to Tollip and the adapters MyD88 and IRAK-4. The interactions of IRAK-1 with MyD88 or Tollip are mediated by the N-terminal part of IRAK-1, containing the death domain with the highly conserved threonine at position 66 (T66). Mutation of this amino acid into alanine or aspartic acid stabilized binding to MyD88, Tollip, and IRAK-4, allowing the definitive experimental proof, that all these interactions are mediated by the death domain of IRAK-1. Homo-oligomerization of IRAK-1, which is mediated by the death domain too, is not affected by mutation of T66. Finally, mutation of IRAK-1 at T66 not only allowed stable binding to the signaling adapters, but also enhanced its signaling capacity.
Neumann
Detlef
D
Department for Pharmacology, Hannover Medical School, Carl-Neuberg-Str 1, D-30623 Hannover, Germany. neumann.detlef@mh-hannover.de
Kollewe
Christian
C
Resch
Klaus
K
Martin
Michael U
MU
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D053218:Receptors, Death Domain / Q000502:physiology*; D015398:Signal Transduction; D013912:Threonine / Q000502:physiology; D013945:Thymoma
D047908:Intracellular Signaling Peptides and Proteins; D053594:Myeloid Differentiation Factor 88; D053218:Receptors, Death Domain; C410602:TOLLIP protein, human; D013912:Threonine; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases