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

Immunity. 2020 Mar 17;52(3):499-512.e5. doi: 10.1016/j.immuni.2020.02.004.

Abstract

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.

Keywords: IL-17; IL-17 signaling; IL-17F; IL-17RC; X-ray structure; cytokine receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Interleukin-17 / chemistry
  • Interleukin-17 / immunology*
  • Interleukin-17 / metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization / immunology*
  • Receptors, Interleukin-17 / chemistry
  • Receptors, Interleukin-17 / immunology*
  • Receptors, Interleukin-17 / metabolism
  • Signal Transduction / immunology*

Substances

  • IL17F protein, human
  • Interleukin-17
  • Receptors, Interleukin-17