Journal article

Publication year: 2003

Pages: 49145-49153

Journal: Journal of Biological Chemistry

Volume number: 278

Issue number: 49

ISSN: 0021-9258

DOI Link: https://doi.org/10.1074/jbc.M306077200

Publisher: Elsevier

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.

Harvard Citation style: Radons, J., Dove, S., Neumann, D., Altmann, R., Botzki, A., Martin, M., et al. (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. https://doi.org/10.1074/jbc.M306077200

APA Citation style: Radons, J., Dove, S., Neumann, D., Altmann, R., Botzki, A., Martin, M., & Falk, W. (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), 49145-49153. https://doi.org/10.1074/jbc.M306077200