title: Structure analysis of the IL-5 ligand-receptor complex reveals a wrench-like architecture for IL-5Rα.
abstract: Interleukin-5 (IL-5) is the key mediator for the function of eosinophil granulocytes, whose deregulation is characteristic of hypereosinophilic diseases and presumably contributes to allergic asthma. IL-5 signaling involves two transmembrane receptors, IL-5Rα and the common β chain, which upon formation of the ternary complex activate the JAK/STAT signaling cascade. To investigate the mechanism underlying ligand-receptor recognition, we determined the structure of IL-5 bound to the extracellular domain of IL-5Rα. IL-5 makes contact with all three fibronectin III-like domains of IL-5Rα, with the receptor architecture resembling a wrench. Mutagenesis data provide evidence that this wrench-like architecture is likely preformed. The structure demonstrates that for steric reasons, homodimeric IL-5 can bind only one receptor molecule, even though two equivalent receptor-binding sites exist. In regard to strong efforts being made to develop IL-5 antagonists for treating asthma and hypereosinophilic diseases, the advances in molecular understanding provided by this structure are of greatest value.
authors.affiliation: Lehrstuhl für Molekulare Pflanzenphysiologie und Biophysik, Julius-von-Sachs Institut der Universität Würzburg, Julius-von-Sachs Platz 2, D-97082 Würzburg, Germany.
authors.forename: Edwin
authors.initials: E
authors.lastname: Patino
authors.forename: Alexander
authors.initials: A
authors.lastname: Kotzsch
authors.forename: Stefan
authors.initials: S
authors.lastname: Saremba
authors.forename: Joachim
authors.initials: J
authors.lastname: Nickel
authors.forename: Werner
authors.initials: W
authors.lastname: Schmitz
authors.forename: Walter
authors.initials: W
authors.lastname: Sebald
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Mueller
mesh_terms: D001665:Binding Sites; D006801:Humans; D015848:Interleukin-5 / Q000737:chemistry* / Q000378:metabolism; D053666:Interleukin-5 Receptor alpha Subunit / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: C508599:IL5 protein, human; C485918:IL5RA protein, human; D015848:Interleukin-5; D053666:Interleukin-5 Receptor alpha Subunit; D008024:Ligands