National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
R01-AI51321
United States
Citation
Journal: Nature / Year: 2022 Title: Organizing structural principles of the IL-17 ligand-receptor axis. Authors: Steven C Wilson / Nathanael A Caveney / Michelle Yen / Christoph Pollmann / Xinyu Xiang / Kevin M Jude / Maximillian Hafer / Naotaka Tsutsumi / Jacob Piehler / K Christopher Garcia / Abstract: The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases. The compositions and structures of functional IL-17 family ...The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases. The compositions and structures of functional IL-17 family ligand-receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 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 responses. Here we studied IL-25-IL-17RB binary and IL-25-IL-17RB-IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25-IL-17RB-IL-17RA ternary signalling 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 imposed by the intracellular domains for signalling. Cryo-electron microscopy 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 among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor.
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