Structural insights into the interaction of IL-33 with its receptors

Xi Liu, Michal Hammel, Yanfeng He, John A. Tainer, U. Ser Jeng, Linqi Zhang, Shuying Wang, Xinquan Wang

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95 Citations (Scopus)


Interleukin (IL)-33 is an important member of the IL-1 family that has pleiotropic activities in innate and adaptive immune responses in host defense and disease. It signals through its ligand-binding primary receptor ST2 and IL-1 receptor accessory protein (IL-1RAcP), both of which are members of the IL-1 receptor family. To clarify the interaction of IL-33 with its receptors, we determined the crystal structure of IL-33 in complex with the ectodomain of ST2 at a resolution of 3.27 Å. Coupled with structure-based mutagenesis and binding assay, the structural results defi ne the molecular mechanism by which ST2 specifically recognizes IL-33. Structural comparison with other ligand-receptor complexes in the IL-1 family indicates that surface-charge complementarity is critical in determining ligand-binding specificity of IL-1 primary receptors. Combined crystallography and small-angle X-ray-scattering studies reveal that ST2 possesses hinge flexibility between the D3 domain and D1D2 module, whereas IL-1RAcP exhibits a rigid conformation in the unbound state in solution. The molecular flexibility of ST2 provides structural insights into domain-level conformational change of IL-1 primary receptors upon ligand binding, and the rigidity of IL-1RAcP explains its inability to bind ligands directly. The solution architecture of IL-33-ST2-IL-1RAcP complex from smallangle X-ray-scattering analysis resembles IL-1β-IL-1RII- IL-1RAcP and IL-1β-IL-1RI-IL-1RAcP crystal structures. The collective results confer IL-33 structure-function relationships, supporting and extending a general model for ligand- receptor assembly and activation in the IL-1 family.

Original languageEnglish
Pages (from-to)14918-14923
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
Publication statusPublished - 2013 Sep 10

All Science Journal Classification (ASJC) codes

  • General

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