IL-22R, IL-10R2, and IL-22BP binding sites are topologically juxtaposed on adjacent and overlapping surfaces of IL-22.
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.
Wu
Paul W
PW
Wyeth Research-Inflammation, Cambridge, MA 02140, USA.
Li
Jing
J
Kodangattil
Sreekumar R
SR
Luxenberg
Deborah P
DP
Bennett
Frann
F
Martino
Margot
M
Collins
Mary
M
Dunussi-Joannopoulos
Kyriaki
K
Gill
Davinder S
DS
Wolfman
Neil M
NM
Fouser
Lynette A
LA
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D053710:Interleukin-10 Receptor beta Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics; D000097043:Interleukin-22
D053710:Interleukin-10 Receptor beta Subunit; D007378:Interleukins; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; D000097043:Interleukin-22; C081846:IL10RB protein, human; C433253:IL22RA2 protein, human; C415369:interleukin-22 receptor