Reconstructing the TIR side of the myddosome: a paradigm for TIR-TIR interactions
- Author
- Laurens Vyncke (UGent) , Celia Bovijn (UGent) , Ewald Pauwels (UGent) , Tim Van Acker (UGent) , Elien Ruyssinck (UGent) , Elianne Burg (UGent) , Jan Tavernier (UGent) and Frank Peelman (UGent)
- Organization
- 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 alpha E-helix, explaining how BB-loop mimetics inhibit MyD88 signaling. The alpha C'-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.
- Keywords
- INTERACTION SITES, 88 MYD88, TOLL-LIKE RECEPTORS, ADAPTER MOLECULE, PROTEIN COMPLEXES, IL-1 RECEPTOR, STRUCTURAL BASIS, CRYSTAL-STRUCTURE, SIGNALING PATHWAY, TOLL/INTERLEUKIN-1 RECEPTOR DOMAINS
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-7242867
- MLA
- Vyncke, Laurens, et al. “Reconstructing the TIR Side of the Myddosome: A Paradigm for TIR-TIR Interactions.” STRUCTURE, vol. 24, no. 3, 2016, pp. 437–47, doi:10.1016/j.str.2015.12.018.
- APA
- Vyncke, L., Bovijn, C., Pauwels, E., Van Acker, T., Ruyssinck, E., Burg, E., … Peelman, F. (2016). Reconstructing the TIR side of the myddosome: a paradigm for TIR-TIR interactions. STRUCTURE, 24(3), 437–447. https://doi.org/10.1016/j.str.2015.12.018
- Chicago author-date
- Vyncke, Laurens, Celia Bovijn, Ewald Pauwels, Tim Van Acker, Elien Ruyssinck, Elianne Burg, Jan Tavernier, and Frank Peelman. 2016. “Reconstructing the TIR Side of the Myddosome: A Paradigm for TIR-TIR Interactions.” STRUCTURE 24 (3): 437–47. https://doi.org/10.1016/j.str.2015.12.018.
- Chicago author-date (all authors)
- Vyncke, Laurens, Celia Bovijn, Ewald Pauwels, Tim Van Acker, Elien Ruyssinck, Elianne Burg, Jan Tavernier, and Frank Peelman. 2016. “Reconstructing the TIR Side of the Myddosome: A Paradigm for TIR-TIR Interactions.” STRUCTURE 24 (3): 437–447. doi:10.1016/j.str.2015.12.018.
- Vancouver
- 1.Vyncke L, Bovijn C, Pauwels E, Van Acker T, Ruyssinck E, Burg E, et al. Reconstructing the TIR side of the myddosome: a paradigm for TIR-TIR interactions. STRUCTURE. 2016;24(3):437–47.
- IEEE
- [1]L. Vyncke et al., “Reconstructing the TIR side of the myddosome: a paradigm for TIR-TIR interactions,” STRUCTURE, vol. 24, no. 3, pp. 437–447, 2016.
@article{7242867,
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 alpha E-helix, explaining how BB-loop mimetics inhibit MyD88 signaling. The alpha C'-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.}},
author = {{Vyncke, Laurens and Bovijn, Celia and Pauwels, Ewald and Van Acker, Tim and Ruyssinck, Elien and Burg, Elianne and Tavernier, Jan and Peelman, Frank}},
issn = {{0969-2126}},
journal = {{STRUCTURE}},
keywords = {{INTERACTION SITES,88 MYD88,TOLL-LIKE RECEPTORS,ADAPTER MOLECULE,PROTEIN COMPLEXES,IL-1 RECEPTOR,STRUCTURAL BASIS,CRYSTAL-STRUCTURE,SIGNALING PATHWAY,TOLL/INTERLEUKIN-1 RECEPTOR DOMAINS}},
language = {{eng}},
number = {{3}},
pages = {{437--447}},
title = {{Reconstructing the TIR side of the myddosome: a paradigm for TIR-TIR interactions}},
url = {{http://doi.org/10.1016/j.str.2015.12.018}},
volume = {{24}},
year = {{2016}},
}
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