Functional Relevance of IL-1 Receptor Inter-domain Flexibility for Cytokine Binding and Signaling

The interleukin 1 (IL-1) receptor family, whose members contain three Ig-like domains (D1-D3) in the extracellular region, is responsible for transmitting pleiotropic signals of IL-1 cytokines. The inter-domain flexibility of IL-1 receptors and its functional roles have not been fully elucidated. In this study, we used small-angle X-ray scattering (SAXS) to show that ligand-binding primary receptors and co-receptors in the family all have inherent inter-domain flexibility due to the D2/D3 linker. Variants of the IL-1RAcP and IL-18Rβ co-receptors with mutated D2/D3 linkers cannot form a cytokine-receptor complex and mediate signaling. Our analysis further revealed that these mutated co-receptors exhibited a changed conformational ensemble, suggesting that loss of function is due to the alteration of receptor dynamics. Taken together, our results demonstrate that the D2/D3 linker is a critical functional determinant of IL-1 receptor and underscore the important roles of the inter-domain flexibility in cytokine/receptor binding and signaling. The IL-1 receptors are responsible for transmitting signaling in immune responses. Jiwan et al. investigated the effect of a common D2/D3 linker within IL-1 receptors and revealed the functional role of inherent inter-domain flexibility in ligand recognition and signal transduction.