7UWL

Structure of the IL-25-IL-17RB-IL-17RA ternary complex

Summary for 7UWL

• Entry DOI: 10.2210/pdb7uwl/pdb
• EMDB information: 26835
• Descriptor: Interleukin-25, Interleukin-17 receptor B, Interleukin-17 receptor A, ... (5 entities in total)
• Functional Keywords: receptor complex, il-17e, il-25, il-17rb, il-17ra, cytokine
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 188850.35

Authors

Wilson, S.C.,Caveney, N.A.,Jude, K.M.,Garcia, K.C. (deposition date: 2022-05-03, release date: 2022-07-27, Last modification date: 2024-10-30)

Primary citation

Wilson, S.C.,Caveney, N.A.,Yen, M.,Pollmann, C.,Xiang, X.,Jude, K.M.,Hafer, M.,Tsutsumi, N.,Piehler, J.,Garcia, K.C.
Organizing structural principles of the IL-17 ligand-receptor axis.
Nature, 609:622-629, 2022

PubMed 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 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.

PubMed: 35863378
DOI: 10.1038/s41586-022-05116-y

Experimental method

ELECTRON MICROSCOPY (3.7 Å)