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Structural Analysis Reveals that the Cytokine IL-17F Forms a Homodimeric Complex with Receptor IL-17RC to Drive IL-17RA-Independent Signaling

Goepfert, Arnaud and Lehmann, Sylvie and Blank, Jutta and Kolbinger, Frank and Rondeau, Jean-Michel (2020) Structural Analysis Reveals that the Cytokine IL-17F Forms a Homodimeric Complex with Receptor IL-17RC to Drive IL-17RA-Independent Signaling. Immunity, 52 (3). 499-512.e5. ISSN 10974180

Abstract

IL-17, a crucial cytokine for chronic inflammatory diseases, forms a heteromeric complex with IL-17RA and IL-17RC receptors for signaling. Goepfert et al. determine the structure of human IL-17F bound to IL-17RC and reveal a homodimeric assembly that contrasts with the prevailing signaling paradigm and suggests IL-17RA-independent roles for IL-17RC.

Interleukin-17A (IL-17A), IL-17F, and IL-17A/F heterodimers are key cytokines of the innate and adaptive immune response. Dysregulation of the IL-17 pathway contributes to immune pathology, and it is therefore important to elucidate the molecular mechanisms that govern IL-17 recognition and signaling. The receptor IL-17RC is thought to act in concert with IL-17RA to transduce IL-17A-, IL-17F-, and IL-17A/F-mediated signals. We report the crystal structure of the extracellular domain of human IL-17RC in complex with IL-17F. In contrast to the expected model, we found that IL-17RC formed a symmetrical 2:1 complex with IL-17F, thus competing with IL-17RA for cytokine binding. Using biophysical techniques, we showed that IL-17A and IL-17A/F also form 2:1 complexes with IL-17RC, suggesting the possibility of IL-17RA-independent IL-17 signaling pathways. The crystal structure of the IL-17RC:IL-17F complex provides a structural basis for IL-17F signaling through IL-17RC, with potential therapeutic applications for respiratory allergy and inflammatory bowel diseases.

Item Type: Article
Keywords: cytokine receptors IL-17 IL-17 signaling IL-17F IL-17RC X-ray structure
Date Deposited: 06 Jun 2020 00:45
Last Modified: 06 Jun 2020 00:45
URI: https://oak.novartis.com/id/eprint/39793

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