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Identification of critical regions within the TIR domain of IL-1 receptor type I

Jürgen Radons1, Werner Falk1, Stefan Dove2

  • 1Department of Internal Medicine I, University Clinic Regensburg, D-93042 Regensburg, Germany.

The International Journal of Biochemistry & Cell Biology
|August 18, 2015
PubMed

Interleukin-1 receptor type I (IL-1RI) belongs to a superfamily of proteins characterized by an intracellular Toll/IL-1 receptor (TIR) domain. This domain harbors three conserved regions called boxes 1-3 that play crucial roles in mediating IL-1 responses. Boxes 1 and 2 are considered to be involved in binding of adapter molecules. Amino acids possibly crucial for IL-1RI signaling were predicted via homology models of the IL-1RI TIR domain based on the crystal structure of IL-1RAPL. The role of ten of these residues was investigated by site-directed mutagenesis and a functional luciferase assay reflecting NF-κB activity in transiently transfected Jurkat cells. In particular, the mutants E437K/D438K, E472A/E473A and S465A/S470A/S471A/E472A/E473A showed decreased and the mutant E437A/D438A increased IL-1 responsiveness compared to the mouse IL-1RI wild type. In conclusion, the αC' helix (Q469-E473 in mouse IL-1RI) is probably involved in heterotypic interactions of IL-1RI with IL-1RAcP or MyD88.

Keywords:
Homology modelingIL-1IL-1RINF-κBSite-directed mutagenesisTIR domain

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