title: Modular organization of Interleukin-6 and Interleukin-11 α-receptors.
abstract: Interleukin (IL)-6 and IL-11 are the only canonical members of the IL-6 family of cytokines that induce signaling through a homodimer of the common β-receptor glycoprotein (gp)130. A pre-requisite for signal transduction is the initial binding of the cytokines to their unique α-receptors, IL-6R and IL-11R. The cell-type specific expression of the two receptors determines the target cells of IL-6 and IL-11, because gp130 is ubiquitously expressed. However, ciliary neurotrophic factor (CNTF) and IL-27p28/IL-30 have been described as additional ligands for the IL-6R, underlining a remarkable plasticity among the cytokines of the IL-6 family and their receptors. In this study, we show that neither IL-6 nor IL-11 can bind to and signal through the α-receptor of the respective other cytokine. We further create eight chimeric IL-6/IL-11 receptors, which are all biologically active. We find that the domains D1 to D3, which contain the cytokine binding module (CBM), determine which cytokine can activate the chimeric receptor, whereas the stalk region, the transmembrane region, or the intracellular region do not participate in the ligand selectivity of the receptor and are therefore interchangeable between IL-6R and IL-11R. These results suggest a modular organization of the IL-6R and IL-11R, and a similar signal transduction complex of the two cytokines.
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225, Düsseldorf, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nitz
authors.affiliation: Institute of Biochemistry, Kiel University, 24118, Kiel, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Lokau
authors.affiliation: Institute of Biochemistry, Kiel University, 24118, Kiel, Germany.
authors.forename: Samadhi
authors.initials: S
authors.lastname: Aparicio-Siegmund
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225, Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Institute of Biochemistry, Kiel University, 24118, Kiel, Germany. Electronic address: cgarbers@biochem.uni-kiel.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism; D053703:Interleukin-11 Receptor alpha Subunit / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053698:Interleukin-6 Receptor alpha Subunit / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D010446:Peptide Fragments / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D019947:Receptors, Interleukin-6 / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C508611:IL11 protein, human; C508428:IL11RA protein, human; C508600:IL6 protein, human; C508603:IL6R protein, human; C494199:IL6ST protein, human; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D015850:Interleukin-6; D053698:Interleukin-6 Receptor alpha Subunit; D008024:Ligands; D010446:Peptide Fragments; D021122:Protein Subunits; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050822:Cytokine Receptor gp130
keywords: Interleukin-11; Interleukin-6; Plasticity; Proliferation; Proteolysis; Signal transduction