Abstract
Interleukin-18 (IL-18), a cytokine formerly known as interferon-γ- (IFN-γ-) inducing factor, has pleiotropic immunoregulatory functions, including augmentation of IFN-γ production, Fas-mediated cytotoxicity and developmental regulation of T-lymphocyte helper type I. We determined the solution structure of IL-18 as a first step toward understanding its receptor activation mechanism. It folds into a β-trefoil structure that resembles that of IL-1. Extensive mutagenesis revealed the presence of three sites that are important for receptor activation: two serve as binding sites for IL-18 receptor α (IL-18Rα), located at positions similar to those of IL-1 for IL-1 receptor type I (IL-1RI), whereas the third site may be involved in IL-18 receptor β (IL-18Rβ) binding. The structure and mutagenesis data provide a basis for understanding the IL-18-induced heterodimerization of receptor subunits, which is necessary for receptor activation.
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Acknowledgements
We thank Y. Matsuo, T. Ikegami, T. Furuya and K. Kasahara for their technical assistance and K. Sukegawa and T. Fukao for critical reading of the manuscript.
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Kato, Z., Jee, J., Shikano, H. et al. The structure and binding mode of interleukin-18. Nat Struct Mol Biol 10, 966–971 (2003). https://doi.org/10.1038/nsb993
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DOI: https://doi.org/10.1038/nsb993
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