Activation of the signal transducer glycoprotein 130 by both IL-6 and IL-11 requires two distinct binding epitopes.
The coordination and regulation of immune responses are primarily mediated by cytokines that bind to specific cell surface receptors. Glycoprotein 130 (gp130) belongs to the family of class I cytokine receptors and is the common signal-transducing receptor subunit shared by the so-called IL-6 type cytokines (IL-6, IL-11, ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M, and cardiotrophin-1). The inflammatory cytokines IL-6 and IL-11 induce gp130 homodimerization after binding to their specific alpha receptors, which leads to the activation of the Janus kinase/STAT signal transduction pathway. A molecular model of IL-6/IL-6R/gp130, which is based on the structure of the growth hormone/growth hormone receptor complex, allowed the selection of several amino acids located in the cytokine-binding module of gp130 for mutagenesis. The mutants were analyzed with regard to IL-6- or IL-11-induced STAT activation and ligand binding. It was found that Y190 and F191 are essential for the interaction of gp130 with IL-6 as well as IL-11, suggesting a common mode of recognition of helical cytokines by class I cytokine receptors. Furthermore, the requirement of the gp130 N-terminal Ig-like domain for ligand binding and signal transduction was demonstrated by the use of deletion mutants. Thus, besides the observed analogy to the growth hormone/growth hormone receptor complex, there is a substantial difference in the mechanism of receptor engagement by cytokines that signal via gp130.
Kurth
I
I
Institut für Biochemie, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.
Horsten
U
U
Pflanz
S
S
Dahmen
H
H
Küster
A
A
Grötzinger
J
J
Heinrich
P C
PC
Müller-Newen
G
G
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D019556:COS Cells; D050822:Cytokine Receptor gp130; D000939:Epitopes / Q000737:chemistry / Q000235:genetics; D006801:Humans; D017370:Interleukin-11 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053703:Interleukin-11 Receptor alpha Subunit; D015850:Interleukin-6 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism; D053702:Receptors, Interleukin-11; D019947:Receptors, Interleukin-6 / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction