The structure and binding mode of interleukin-18.
Interleukin-18 (IL-18), a cytokine formerly known as interferon-gamma- (IFN-gamma-) inducing factor, has pleiotropic immunoregulatory functions, including augmentation of IFN-gamma 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 beta-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 alpha (IL-18Ralpha), 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 beta (IL-18Rbeta) 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.
Kato
Zenichiro
Z
Department of Pediatrics, Gifu University School of Medicine, Tsukasa 40, Gifu 500-8705, Japan. zen-k@cc.gifu-u.ac.jp
Jee
JunGoo
J
Shikano
Hiroaki
H
Mishima
Masaki
M
Ohki
Izuru
I
Ohnishi
Hidenori
H
Li
Ailian
A
Hashimoto
Kazuyuki
K
Matsukuma
Eiji
E
Omoya
Kentaro
K
Yamamoto
Yutaka
Y
Yoneda
Teruyo
T
Hara
Takane
T
Kondo
Naomi
N
Shirakawa
Masahiro
M
D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D020382:Interleukin-18 / Q000737:chemistry* / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit; D008969:Molecular Sequence Data; D018123:Receptors, Interleukin / Q000378:metabolism; D053724:Receptors, Interleukin-18
C508572:IL18R1 protein, human; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18