Organizing Structural Principles of the Interleukin-17 Ligand-Receptor Axis – Nature

The interleukin-17 (IL-17) family of cytokines and receptors play central roles in host defense against infection, and development of inflammatory diseases¹. The compositions and structures of functional IL-17 family ligand-receptor signaling assemblies remain unclear. Interleukin-17E (IL-17E or IL-25) is a key regulator of Th2 immune responses and driver of inflammatory diseases such as allergic asthma and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses². Here, we studied IL-25–IL-17RB binary and IL-25–IL-17RB–IL-17RA ternary complexes using a combination of cryo-electron microscopy (cryo-EM), single-molecule imaging, and cell-based signaling approaches. The IL-25–IL-17RB–IL-17RA ternary signaling assembly is a c2-symmetric complex in which the IL-25–IL-17RB homodimer is flanked by two “wing-like” IL-17RA co-receptors through a “tip-to-tip” geometry that is the key receptor-receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB–IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints by the intracellular domains for signaling. Cryo-EM structures of IL-17A–IL-17RA and IL-17A–IL-17RA–IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family, Furthermore, these studies reveal dual actions for IL-17RA sharing amongst IL-17 cytokine complexes, by either directly engaging IL-17 cytokines, or alternatively functioning as a co-receptor.