Structural basis of receptor sharing by interleukin 17 cytokines

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Abstract
The interleukin 17 (IL-17) family includes six cytokines and five receptors. Garcia and co-workers solve the crystal structure of the receptor IL-17RA bound to IL-17F and suggest that IL-17RA may act as a shared subunit among multiple IL-17 receptor complexes. Interleukin 17 (IL-17)-producing helper T cells (TH-17 cells), together with their effector cytokines, including members of the IL-17 family, are emerging as key mediators of chronic inflammatory and autoimmune disorders. Here we present the crystal structure of a complex of IL-17 receptor A (IL-17RA) bound to IL-17F in a 1:2 stoichiometry. The mechanism of complex formation was unique for cytokines and involved the engagement of IL-17 by two fibronectin-type domains of IL-17RA in a groove between the IL-17 homodimer interface. Binding of the first receptor to the IL-17 cytokines modulated the affinity and specificity of the second receptor-binding event, thereby promoting heterodimeric versus homodimeric complex formation. IL-17RA used a common recognition strategy to bind to several members of the IL-17 family, which allows it to potentially act as a shared receptor in multiple different signaling complexes.