1. Functional Relevance of Interleukin-1 Receptor Inter-domain Flexibility for Cytokine Binding and Signaling
- Author
-
Ge, Jiwan, Remesh, Soumya G, Hammel, Michal, Pan, Si, Mahan, Andrew D, Wang, Shuying, and Wang, Xinquan
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Amino Acid Sequence ,Animals ,Binding Sites ,Cell Line ,Humans ,Models ,Molecular ,Mutation ,Protein Binding ,Protein Conformation ,Protein Domains ,Receptors ,Interleukin-1 ,Scattering ,Small Angle ,Sf9 Cells ,Signal Transduction ,X-Ray Diffraction ,IL-1 receptor family ,dual-luciferase reporter assay ,inter-domain flexibility ,minimal ensemble search ,signal transduction ,small-angle X-ray scattering ,Biophysics - Abstract
The interleukin 1 (IL-1) receptor family, whose members contain three immunoglobulin-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 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.
- Published
- 2019