The death domain of IRAK-1: an oligomerization domain mediating interactions with MyD88, Tollip, IRAK-1, and IRAK-4

Biochem Biophys Res Commun. 2007 Mar 23;354(4):1089-94. doi: 10.1016/j.bbrc.2007.01.104. Epub 2007 Jan 26.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line, Tumor
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / genetics*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Myeloid Differentiation Factor 88 / metabolism*
  • Protein Structure, Tertiary
  • Receptors, Death Domain / physiology*
  • Signal Transduction
  • Threonine / physiology
  • Thymoma

Substances

  • Intracellular Signaling Peptides and Proteins
  • Myeloid Differentiation Factor 88
  • Receptors, Death Domain
  • TOLLIP protein, human
  • Threonine
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases