Radons, Jürgen and Dove, Stefan and Neumann, Detlef and Altmann, Reinhold and Botzki, Alexander and Martin, Michael U. and Falk, Werner (2003) The interleukin 1 (IL-1) receptor accessory protein Toll/IL-1 receptor domain - Analysis of putative interaction sites by in vitro mutagenesis and molecular modeling. JOURNAL OF BIOLOGICAL CHEMISTRY, 278 (49). pp. 49145-49153. ISSN 0021-9258, 1083-351X
Full text not available from this repository. (Request a copy)Abstract
The Toll/interleukin 1 (IL-1) receptor family plays an important role in both innate and adaptive immunity. These receptors are characterized by a C-terminal homology motif called the Toll/IL-1 receptor (TIR) domain. A principal function of the TIR domain is mediating homotypic protein-protein interactions in the signal transduction pathway. To suggest interaction sites of TIR domains in the IL-1 receptor complex, we modeled the putative three-dimensional structure of the TIR domain within the co-receptor chain, IL-1 receptor accessory protein. The model was based on homology with the crystal structures of human TLR1 and TLR2. The final structure of the IL-1 receptor accessory protein TIR domain suggests the conserved regions box 1 and 2, including Pro-446, as well as box 3 within the C-terminal alpha-helix as possible protein-protein interaction sites due to their exposure and their electrostatic potential. Pro-446, corresponding to the Pro/His mutation in dominant negative TLR4, is located in the third loop at the outmost edge of the TIR domain and does not play any structural role. Inhibition of IL-1 responsiveness seen after substitution of Pro-446 by charged amino acids is due to the loss of an interaction site for other TIR domains. Amino acids 527 - 534 as part of the loop close to the conserved box 3 are critical for recruitment of myeloid differentiation factor 88 and to a lesser extent for IL-1 responsiveness. Modeling suggests that native folding of the TIR domain may be approached by the responsive deletion mutants Delta528 - 534 and Delta527 - 533, whereas the C-terminal beta-strand and/or alpha-helix is displaced in the nonresponsive mutant Delta527 - 534.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; TOLL-LIKE RECEPTOR-3; DOUBLE-STRANDED-RNA; SIGNAL-TRANSDUCTION PATHWAY; PHOSPHATIDYLINOSITOL 3-KINASE; ADAPTER PROTEIN; IRAK FAMILY; KINASE IRAK; MAP KINASE; ACTIVATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine 600 Technology > 615 Pharmacy |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Jul 2021 10:05 |
| Last Modified: | 27 Jul 2021 10:05 |
| URI: | https://pred.uni-regensburg.de/id/eprint/38318 |
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