IL-22R, IL-10R2, and IL-22BP Binding Sites Are Topologically Juxtaposed on Adjacent and Overlapping Surfaces of IL-22

• Published in: Journal of molecular biology 2008-10, Vol.382 (5), p.1168-1183
• Main Authors: Wu, Paul W., Li, Jing, Kodangattil, Sreekumar R., Luxenberg, Deborah P., Bennett, Frann, Martino, Margot, Collins, Mary, Dunussi-Joannopoulos, Kyriaki, Gill, Davinder S., Wolfman, Neil M., Fouser, Lynette A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Binding Sites - genetics; Cell Line; Humans; IL-10R2; IL-22; IL-22BP; IL-22R; In Vitro Techniques; Interleukin-10 Receptor beta Subunit - chemistry; Interleukin-10 Receptor beta Subunit - genetics; Interleukin-10 Receptor beta Subunit - metabolism; Interleukin-22; Interleukins - chemistry; Interleukins - genetics; Interleukins - metabolism; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Protein Conformation; Protein Folding; Protein Structure, Secondary; Receptors, Interleukin - chemistry; Receptors, Interleukin - genetics; Receptors, Interleukin - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Sequence Homology, Amino Acid; structure/function; Thermodynamics
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2008.07.046

Interleukin (IL) 22 is a type II cytokine that is produced by immune cells and acts on nonimmune cells to regulate local tissue inflammation. As a product of the recently identified T helper 17 lineage of CD4 + effector lymphocytes, IL-22 plays a critical role in mucosal immunity as well as in dysregulated inflammation observed in autoimmune diseases. We used comprehensive mutagenesis combined with mammalian cell expression, ELISA cell-based, and structural methods to evaluate how IL-22 interacts with its cell surface receptor, IL-22R/IL-10R2, and with secreted IL-22 binding protein. This study identifies those amino acid side chains of IL-22 that are individually important for optimal binding to IL-22R, considerably expands the definition of IL-22 surface required for binding to IL-10R2, and demonstrates how IL-22 binding protein prevents IL-22R from binding to IL-22. The IL-22R and IL-10R2 binding sites are juxtaposed on adjacent IL-22 surfaces contributed mostly by helices A, D, and F and loop AB. Our results also provide a model for how IL-19, IL-20, IL-24, and IL-26 which are other IL-10-like cytokines, interact with their respective cell surface receptors.