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

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.