Organizing structural principles of the IL-17 ligand–receptor axis

Steven C. Wilson, Nathanael A. Caveney, Michelle Yen, Christoph Pollmann, Xinyu Xiang, Kevin M. Jude, Maximillian Hafer, Naotaka Tsutsumi, Jacob Piehler and K. Christopher Garcia ()
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Steven C. Wilson: Stanford University School of Medicine
Nathanael A. Caveney: Stanford University School of Medicine
Michelle Yen: Stanford University School of Medicine
Christoph Pollmann: University of Osnabrück
Xinyu Xiang: Stanford University School of Medicine
Kevin M. Jude: Stanford University School of Medicine
Maximillian Hafer: University of Osnabrück
Naotaka Tsutsumi: Stanford University School of Medicine
Jacob Piehler: University of Osnabrück
K. Christopher Garcia: Stanford University School of Medicine

Nature, 2022, vol. 609, issue 7927, 622-629

Abstract: Abstract The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases1. 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 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, 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.

Date: 2022
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DOI: 10.1038/s41586-022-05116-y

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