Reconstructing the TIR Side of the Myddosome: a Paradigm for TIR-TIR Interactions

Structure. 2016 Mar 1;24(3):437-47. doi: 10.1016/j.str.2015.12.018. Epub 2016 Feb 11.

Abstract

Members of the Toll-like receptor and interleukin-1 (IL-1) receptor families all signal via Toll/IL-1R (TIR) domain-driven assemblies with adaptors such as MyD88. We here combine the mammalian two-hybrid system MAPPIT and saturation mutagenesis to complement and extend crystallographic and nuclear magnetic resonance data, and reveal how TIR domains interact. We fully delineate the interaction sites on the MyD88 TIR domain for homo-oligomerization and for interaction with Mal and TLR4. Interactions between three sites drive MyD88 homo-oligomerization. The BB-loop interacts with the αE-helix, explaining how BB-loop mimetics inhibit MyD88 signaling. The αC'-helix interacts symmetrically. The MyD88 TIR domains thus assemble into a left-handed helix, compatible with the Myddosome death domain crystal structure. This assembly explains activation of MyD88 by Mal and by an oncogenic mutation, and regulation by phosphorylation. These findings provide a paradigm for the interaction of mammalian TIR domains.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Mutation*
  • Myelin and Lymphocyte-Associated Proteolipid Proteins / metabolism*
  • Myeloid Differentiation Factor 88 / chemistry*
  • Myeloid Differentiation Factor 88 / genetics*
  • Myeloid Differentiation Factor 88 / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • Protein Multimerization
  • Protein Structure, Secondary
  • Toll-Like Receptor 4 / metabolism

Substances

  • MAL protein, human
  • MYD88 protein, human
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Myeloid Differentiation Factor 88
  • TLR4 protein, human
  • Toll-Like Receptor 4