1. Reconstructing the TIR Side of the Myddosome: a Paradigm for TIR-TIR Interactions
- Author
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Elien Ruyssinck, Tim Van Acker, Jan Tavernier, Frank Peelman, Laurens Vyncke, Elianne Burg, Celia Bovijn, and Ewald Pauwels
- Subjects
Models, Molecular ,0301 basic medicine ,Protein domain ,Plasma protein binding ,Biology ,Protein Structure, Secondary ,03 medical and health sciences ,Protein structure ,Protein Domains ,Structural Biology ,Humans ,Phosphorylation ,Binding site ,Saturated mutagenesis ,Molecular Biology ,Death domain ,Binding Sites ,Myelin and Lymphocyte-Associated Proteolipid Proteins ,Cell biology ,Molecular Docking Simulation ,Toll-Like Receptor 4 ,HEK293 Cells ,030104 developmental biology ,Mutation ,Myeloid Differentiation Factor 88 ,Helix ,Protein Multimerization ,Signal transduction ,Protein Binding - 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.
- Published
- 2016
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