Structural insights into the assembly and activation of the IL-27 signaling complex

Yibo Jin, Paul K. Fyfe, Scott Gardner, Stephan Wilmes, Doryen Bubeck (Lead / Corresponding author), Ignacio Moraga (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
76 Downloads (Pure)


Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.

Original languageEnglish
Article numbere55450
Number of pages10
JournalEMBO Reports
Issue number10
Early online date3 Aug 2022
Publication statusPublished - 6 Oct 2022


  • GP130
  • IL-27
  • cryo electron microscopy
  • cytokine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


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