The Crystal Structure of the IL-33 Signaling Complex Reveals the Molecular Basis for Receptor Sharing in the IL-1 Family.

Cytokines of the IL-1 family are potent stimulators of the immune system. As seen in other cytokine families, cytokine redundancy due to receptor sharing is characteristic for the IL-1 family. Today five primary receptors have been described that each bind a subset of the 11 known cytokines within this family. Once an agonistic cytokine-receptor pair has formed, it can engage one of the two co-receptors and initiate signaling through MyD88. While IL-18Rβ is the unique co-receptor for the IL-18/IL-18Rα pair, IL-1RAcP is shared between the other four primary receptors, IL-1RI, IL-1RII, ST2 and IL-36R. Crystal structures of IL-1β bound to IL-1RI or IL-1RII in complex with IL-1RAcP previously revealed the general architecture of signaling complexes in the IL-1 family. IL-33 is the latest cytokine to be discovered in the IL-1 family. Since its first description in 2005 it has been recognized as a central driver of type 2 immunity. Here we present the crystal structure of IL-33 in complex with its receptors ST2 and IL-1RAcP. The structure reveals a remarkable conservation of the ternary architecture of signaling complexes in the IL-1 family. We observe common principles of co-receptor binding, also seen in the other two ternary structures containing IL-1RAcP. However, hydrogen/deuterium mass exchange spectroscopy and extensive alanine-scanning analysis combined with direct binding analysis of the IL-1β and IL-33 signaling complexes demonstrate that the binding energy is distributed quite differently within the two. Co-receptor binding of ST2/IL-33 is much less dependent on the cytokine than on the receptor, while for IL-1β/IL-1RI the cytokine plays a much more important role.