Characterization of the interaction between interleukin-13 and interleukin-13 receptors

Interleukin-13 (IL-13) possesses two types of receptor: the heterodimer, composed of the IL-13R alpha 1 chain (IL-13R alpha 1) and the IL-4R alpha chain (IL-4R alpha), transducing the IL-13 signals; and the IL-13R alpha 2 chain (IL-13R alpha 2), acting as a nonsignaling decoy receptor. Extracellular portions of both IL-13R alpha 1 and IL-13R alpha 2 are composed of three fibronectin type III domains, D1, D2, and D3, of which the last two comprise the cytokine receptor homology modules (CRHs), a common structure of the class I cytokine receptor superfamily. Thus far, there has been no information about the critical amino acids of the CRHs or the role of the D1 domains of IL-13R alpha 1 and IL-13R alpha 2 in binding to IL-13. In this study, we first built the homology modeling of the IL-13(.)hIL-13 receptor complexes and then predicted the amino acids involved in binding to IL-13. By incorporating mutations into these amino acids, we identified Tyr-207, Asp-271, Tyr-315, and Asp-318 in the CRH of human IL-13R alpha 2, and Leu-319 and Tyr-321 in the CRH of human IL-13R alpha 1, as critical residues for binding to IL-13. Tyr-315 in IL-13R alpha 2 and Leu-319 in IL-13R alpha 1 are positionally conserved hydrophobic amino acid residues. Furthermore, by using D1 domain-deleted mutants, we found that the D1 domain is needed for the expression of IL-13R alpha 2, but not IL-13R alpha 1, and that the D1 domain of IL-13R alpha 1 is important for binding to IL-13, but not to IL-4. These results provide the basis for a precise understanding of the interaction between IL-13 and its receptors.