title: Activation of the signal transducer glycoprotein 130 by both IL-6 and IL-11 requires two distinct binding epitopes.
abstract: 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.
authors.affiliation: Institut für Biochemie, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Kurth
authors.forename: U
authors.initials: U
authors.lastname: Horsten
authors.forename: S
authors.initials: S
authors.lastname: Pflanz
authors.forename: H
authors.initials: H
authors.lastname: Dahmen
authors.forename: A
authors.initials: A
authors.lastname: Küster
authors.forename: J
authors.initials: J
authors.lastname: Grötzinger
authors.forename: P C
authors.initials: PC
authors.lastname: Heinrich
authors.forename: G
authors.initials: G
authors.lastname: Müller-Newen
mesh_terms: 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