Structural biology of the IL-1 superfamily: key cytokines in the regulation of immune and inflammatory responses

Abstract

Interleukin-1 superfamily of cytokines (IL-1, IL-18, IL-33) play key roles in inflammation and regulating immunity. The mechanisms of agonism and antagonism in the IL-1 superfamily have been pursued by structural biologists for nearly 20 years. New insights into these mechanisms were recently provided by the crystal structures of the ternary complexes of IL-1β and its receptors. We will review here the structural biology related to receptor recognition by IL-1 superfamily cytokines and the regulation of its cytokine activities by antagonists.

Keywords: agonist; antagonist; cytokine; inflammation; interleukin; receptors.

Figure 1

Cartoon representation of IL-1 superfamily signaling. A: IL-1 signaling is initiated by the ternary complex formation of IL-1α/β:IL-1RI:IL-1RAcP. The decoy receptor IL-1RII lacks an intracellular TIR domain and forms a non-signaling ternary complex with IL-1α/β and IL-1RAcP. The receptor antagonist IL-1Ra binds IL-1RI and forms an inhibitory binary complex that fails to recruit IL-1RAcP. B) IL-18 signaling complex involves IL-18, IL-18Rα and IL-18Rβ. Antagonism is achieved through binding of IL-18BP to IL-18. C) IL-33 signaling involves IL-33, IL-33Rα and IL-1RAcP. The ectodomains of IL-1 superfamily receptors each contains three Ig-like domains, which are labeled as D1, D2, and D3 respectively.

Figure 2

Structures of IL-1 superfamily cytokines. Cytokines of the IL-1 superfamily adopt a conserved β-trefoil fold. PDB files displayed: IL-1α:2KKI, IL-1β:1I1B, IL-1Ra:1ILR, IL-18:1J0S, IL-33:2KLL.

Figure 3

Receptor binding sites on IL-1β, IL-18, and IL-33. Depicted are the secondary structures (top) and the electropotential surfaces (bottom) of IL-1β (A and D, PDB ID 1ITB), IL-18 (B and E, PDB ID 4EKX) and IL-33 (C and F, PDB ID 4KC3). Residues that have been shown to interact with their respective receptors are shown as spheres and colored in red and orange for site A (site I for IL-18 and IL-33) and site B (site II for IL-18 and IL-33), respectively. A third putative receptor-binding site (site III) on IL-18 is shown as blue spheres. The surface area of the binding site A (site I) is indicated as a red circle on each cytokine (bottom).

Figure 4

A common binding mode for receptor:ligand binary complexes. A: IL-1Ra (red) binds IL-1RI (yellow) predominantly at site A, with minimal interactions with the D3 domain of IL-1RI (PDB ID 1IRA). B) The binary complex of IL-1β (green):IL-1RI (cyan) revealed two binding sites, shown as spheres and colored in red (site A) and orange (site B), respectively (PDB ID 1ITB). C) The binary complex of IL-33 (magenta):IL-33Rα (blue) (PDB ID 4KC3). The receptor binding sites I and II on IL-33 are shown as red and orange spheres, respectively. D) and E) Rotation of the D3 domains of IL-1RI in different binary complexes. D) Superimposition of the structures of IL-1Ra:IL-1RI and IL-1β:IL-1RI reveals an approximate 20⁰ rotation between the D3 domains of IL-1RI in the respective structures. E) The D3 domains of the respective receptors in IL-33:IL-33Rα and IL-1Ra:IL-1RI complexes display an approximate 10⁰ rotation. The coloring schemes for the D3 domains of IL-1RI and IL-33Rα are same as above.

Figure 5

Ternary complex structures of IL-1β and its receptors. A) Superimposition of the non-signaling complex [IL-1β (Green):IL-1RII (Magenta):IL-1RAcP (Cyan), PDB ID:3O4O] and the signaling Complex [IL-1β (Yellow):IL-1RI (Pink):IL-1RAcP (Silver) PDB ID:4DEP]. B) Zoom-in view of the D3-D3 domain interactions of IL-1RAcP:IL-1RI and IL-1RAcP:IL-1RII. IL-1β is removed for clarity. The signaling complex showed additional interactions (residues shown in sticks) between IL-1RAcP with IL-1RI due to further rotation of the D3 domain of IL-1RI. These interactions were not observed between IL-1RAcP and IL-1RII in the non-signaling complex. C) Zoom-in view of the additional interactions between IL-1β and IL-1RAcP in the signaling ternary complex. Residue T300 of IL-1RAcP is involved in exquisite interactions with residues D54, I104, E105 and I106 of IL-1β.

Figure 6

Unresolved questions regarding IL-18 subfamily signaling. A) IL-1R signaling ternary complex. IL-1β, IL-1RI and IL-1RAcP are colored in green, cyan and magenta (PDB ID 4DEP). Binding sites A and B are shown in red and orange spheres, respectively. B) A model of IL-18 (yellow):IL-18Rα (cyan):IL-18Rβ (magenta) based on the structure of IL-1β:IL-1RI:IL-1RAcP ternary complex. Putative receptor binding sites I (grey), II (grey) and III (blue) on IL-18 are shown as spheres. Notice site III is not involved in binding of either IL-18R in this model.

Figure 7

Mechanism of antagonism of IL-18 signaling by IL-18BP. A) The inhibitory complex of ectromelia virus (ectv) IL-18BP (yellow) and human IL-18 (hIL-18, cyan) in a 1:1 stoichiometry (PDB ID 3F62). B) The inhibitory complex of yaba-like disease virus (yldv) IL-18BP (green and magenta) and hIL-18 (yellow and cyan) in a 2:2 stoichiometry (PDB ID 4EKX). There is an intra-molecular disulfide bond within the yldv-IL-18BP homodimer as shown in orange spheres. C) Ectv-IL-18BP blocks the putative receptor-binding site II. Ectv-IL-18BP is shown as yellow ribbon with the key residues at the interface highlighted shown as sticks. Putative receptor binding sites I, II, and III on hIL-18 (cyan) are shown as spheres and colored in red, orange, and blue, respectively. Residues shared for binding with both IL-18Rα and ectvIL-18BP are shown as purple spheres.