Crystal structures of interleukin 17A and its complex with IL-17 receptor A

• Published in: Nature communications Vol. 4; no. 1; p. 1888
• Main Authors: Liu, Shenping, Song, Xi, Chrunyk, Boris A., Shanker, Suman, Hoth, Lise R., Marr, Eric S., Griffor, Matthew C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2013; Nature Publishing Group
• Subjects: 631/250/127/1213; 631/535; Allosteric Regulation; Amino Acid Sequence; Conserved Sequence; Crystallization; Crystallography, X-Ray; HEK293 Cells; Humanities and Social Sciences; Humans; Interleukin-17 - chemistry; Interleukin-17 - metabolism; Models, Molecular; Molecular Sequence Data; multidisciplinary; Mutagenesis; Protein Binding; Protein Multimerization; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, Interleukin-17 - chemistry; Receptors, Interleukin-17 - metabolism; Science; Science (multidisciplinary); Surface Plasmon Resonance
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2880

The constituent polypeptides of the interleukin-17 family form six different homodimeric cytokines (IL-17A–F) and the heterodimeric IL-17A/F. Their interactions with IL-17 receptors A–E (IL-17RA–E) mediate host defenses while also contributing to inflammatory and autoimmune responses. IL-17A and IL-17F both preferentially engage a receptor complex containing one molecule of IL-17RA and one molecule of IL-17RC. More generally, IL-17RA appears to be a shared receptor that pairs with other members of its family to allow signaling of different IL-17 cytokines. Here we report crystal structures of homodimeric IL-17A and its complex with IL-17RA. Binding to IL-17RA at one side of the IL-17A molecule induces a conformational change in the second, symmetry-related receptor site of IL-17A. This change favors, and is sufficient to account for, the selection of a different receptor polypeptide to complete the cytokine-receptor complex. The structural results are supported by biophysical studies with IL-17A variants produced by site-directed mutagenesis.
Interleukin-17A homodimers preferentially interact with heterodimeric IL-17 receptors. By solving the crystal structure of an IL-17A homodimer in complex with a single IL-17RA receptor subunit, the authors reveal conformational changes in IL-17A that lead to exclusion of a second IL-17RA subunit.