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Structure analysis of the IL-5 ligand-receptor complex reveals a wrench-like architecture for IL-5R alpha
: Patino, E.; Kotzsch, A.; Saremba, S.; Nickel, J.; Schmitz, W.; Sebald, W.; Mueller, T.D.
|Structure 19 (2011), No.12, pp.1864-1875|
| Journal Article|
|Fraunhofer IGB ()|
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-5R alpha and the common beta 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-5R alpha. IL-5 makes contact with all three fibronectin III-like domains of IL-5R alpha, 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 fortreating asthma and hypereosinophilic diseases, the advances in molecular understanding provided by this structure are of greatest value.