Sequential binding mechanism in the IL-4/-13 receptor activation. (a) The binding of IL-4 to its cellular receptor follows a two-step sequential binding mechanism. First, IL-4 is recruited to the membrane by its high-affinity subunit IL-4Rα; second, either one of the two low affinity subunits IL-13Rα1 (apparent K
D ~ 1 μM) or γc (app. K
D ~ 1.5 – 2 μM) is recruited into the complex. (b) For IL-13 the order of the binding events is reversed. IL-13 binds first to the IL-13Rα1 subunit; the affinity of IL-13 to IL-4Rα is below detection limit (app. K
D > 100 μM). In the second step the IL-13:IL-13Rα1 complex recruits the IL-4Rα subunit into the complex. Values marked K
D* indicate that these interactions are measured by binding of the soluble ectodomain to the surface immobilized binary complex of ligand and high-affinity receptor subunits. These apparent binding constants do not reflect the real affinity for a two-dimensional interaction in the membrane. (c, d) The location of the binding sites for the receptor subunits IL-4Rα and IL-13Rα1 are conserved between the two cytokines IL-4 (c) and IL-13 (d). Site 1 is used for the interaction with the IL-4Rα subunit, site 2 is used for the interaction with IL-13Rα1 (and for binding to γc in the case of IL-4).