The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties

• Published in: Scientific reports Vol. 7; no. 1; pp. 8906 - 13
• Main Authors: Goepfert, Arnaud, Lehmann, Sylvie, Wirth, Emmanuelle, Rondeau, Jean-Michel
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 21.08.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adaptive immunity; Affinity; Allosteric Regulation; Amino Acid Sequence; Arthritis; Autoimmune diseases; Binding Sites; Conserved Sequence; Crystal structure; Cytokines; Cytokines - chemistry; Cytokines - metabolism; Humans; Hydrophobic and Hydrophilic Interactions; Interleukin 17; Interleukin-17 - chemistry; Interleukin-17 - metabolism; Mimicry; Models, Molecular; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization; Psoriasis; Psoriatic arthritis; Receptors, Interleukin-17 - metabolism; Site-directed mutagenesis; Structure-Activity Relationship
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-08360-9

IL-17A and IL-17F are prominent members of the IL-17 family of cytokines that regulates both innate and adaptive immunity. IL-17A has been implicated in chronic inflammatory and autoimmune diseases, and anti-IL-17A antibodies have shown remarkable clinical efficacy in psoriasis and psoriatic arthritis patients. IL-17A and IL-17F are homodimeric cytokines that can also form the IL-17A/F heterodimer whose precise role in health and disease remains elusive. All three cytokines signal through the assembly of a ternary complex with the IL-17RA and IL-17RC receptors. Here we report the X-ray analysis of the human IL-17A/F heterodimer that reveals a two-faced cytokine closely mimicking IL-17A as well as IL-17F. We also present the crystal structure of its complex with the IL-17RA receptor. Unexpectedly in view of the much higher affinity of this receptor toward IL-17A, we find that IL-17RA is bound to the "F-face" of the heterodimer in the crystal. Using site-directed mutagenesis, we then demonstrate that IL-17RA can also bind to the "A-face" of IL-17A/F with similar affinity. Further, we show that IL-17RC does not discriminate between the two faces of the cytokine heterodimer either, thus enabling the formation of two topologically-distinct heterotrimeric complexes with potentially different signaling properties.