title: Crystal structures of interleukin 17A and its complex with IL-17 receptor A.
abstract: 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.
authors.affiliation: Structural Biology and Biophysics Group, Pfizer Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA. shenping.liu@pfizer.com
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.forename: Xi
authors.initials: X
authors.lastname: Song
authors.forename: Boris A
authors.initials: BA
authors.lastname: Chrunyk
authors.forename: Suman
authors.initials: S
authors.lastname: Shanker
authors.forename: Lise R
authors.initials: LR
authors.lastname: Hoth
authors.forename: Eric S
authors.initials: ES
authors.lastname: Marr
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Griffor
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D020381:Interleukin-17 / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D053722:Receptors, Interleukin-17 / Q000737:chemistry* / Q000378:metabolism; D020349:Surface Plasmon Resonance
chemical_list: D020381:Interleukin-17; D053722:Receptors, Interleukin-17