| Literature DB >> 26876098 |
Laurens Vyncke1, Celia Bovijn1, Ewald Pauwels2, Tim Van Acker1, Elien Ruyssinck1, Elianne Burg1, Jan Tavernier1, Frank Peelman3.
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.Entities:
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Year: 2016 PMID： 26876098 DOI： 10.1016/j.str.2015.12.018
Source DB: PubMed Journal: Structure ISSN： 0969-2126 Impact factor: 5.006