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J Biol Chem. 2012 Feb 3;287(6):4088-98. doi: 10.1074/jbc.M111.282350. Epub 2011 Dec 2.

Identification of interaction sites for dimerization and adapter recruitment in Toll/interleukin-1 receptor (TIR) domain of Toll-like receptor 4.

Author information

1
Department of Medical Protein Research, Unit of Molecular Signal Transduction in Inflammation, Flanders Interuniversity Institute for Biotechnology, Ghent University, B-9000 Ghent, Belgium.

Abstract

Toll-like receptor signaling requires interactions of the Toll/IL-1 receptor (TIR) domains of the receptor and adapter proteins. Using the mammalian protein-protein interaction trap strategy, homology modeling, and site-directed mutagenesis, we identify the interaction surfaces in the TLR4 TIR domain for the TLR4-TLR4, TLR4-MyD88 adapter-like (MAL), and TLR4-TRIF-related adapter molecule (TRAM) interaction. Two binding sites are equally important for TLR4 dimerization and adapter recruitment. In a model based on the crystal structure of the dimeric TLR10 TIR domain, the first binding site mediates TLR4-TLR4 TIR-TIR interaction. Upon dimerization, two identical second binding sites of the TLR4 TIR domain are juxtaposed and form an extended binding platform for both MAL and TRAM. In our mammalian protein-protein interaction trap assay, MAL and TRAM compete for binding to this platform. Our data suggest that adapter binding can stabilize the TLR4 TIR dimerization.

PMID:
22139835
PMCID:
PMC3281722
DOI:
10.1074/jbc.M111.282350
[Indexed for MEDLINE]
Free PMC Article

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