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.

白介素-17A（IL-17A），IL-17F和IL-17A / F异二聚体是先天性和适应性免疫应答的关键细胞因子。IL-17通路的失调有助于免疫病理学，因此阐明控制IL-17识别和信号传导的分子机制非常重要。认为IL-17RC受体与IL-17RA协同作用，以转导IL-17A-，IL-17F-和IL-17A / F介导的信号。我们报告与IL-17F复杂的人类IL-17RC胞外域的晶体结构。与预期的模型相反，我们发现IL-17RC与IL-17F形成对称的2：1复合物，从而与IL-17RA竞争细胞因子的结合。使用生物物理技术，我们显示IL-17A和IL-17A / F也与IL-17RC形成2：1的复合物，这提示了独立于IL-17RA的IL-17信号通路的可能性。