Structure of the IL-27 quaternary receptor signaling complex
Interleukin 27 (IL-27) is a heterodimeric cytokine that functions to constrain T cell-mediated inflammation and plays an important role in immune homeostasis. Binding of IL-27 to cell surface receptors IL-27Rα and gp130 results in activation of receptor-associated Janus Kinases and nuclear translocation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT3 transcription factors. Despite the emerging therapeutic importance of this cytokine axis in cancer and autoimmunity, a molecular blueprint of the IL-27 receptor signaling complex, and its relation to other gp130/IL-12 family cytokines, is currently unclear. We used cryogenic-electron microscopy to determine the quaternary structure of IL-27, composed of p28 and Ebi3 subunits, bound to receptors, IL-27Rα and gp130. The resulting 3.47 Å resolution structure revealed a three-site assembly mechanism nucleated by the central p28 subunit of the cytokine. The overall topology and molecular details of this binding are reminiscent of IL-6 but distinct from related heterodimeric cytokines IL-12 and IL-23. These results indicate distinct receptor assembly mechanisms used by heterodimeric cytokines with important consequences for targeted agonism and antagonism of IL-27 signaling.
CryoEM maps and atomic coordinates for human IL-27 quaternary complex have been deposited in the EMDB (EMD- 26382) and PDB (7U7N) respectively.
IL-27 quaternary receptor signaling complexProtein Data Bank, 7U7N.
Article and author information
Canadian Institutes of Health Research
- Nathanael A Caveney
Howard Hughes Medical Institute
- K Christopher Garcia
National Institute of Allergy and Infectious Diseases (R01-AI51321)
- K Christopher Garcia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Andrew C Kruse, Harvard Medical School, United States
- Received: March 8, 2022
- Preprint posted: March 9, 2022 (view preprint)
- Accepted: May 16, 2022
- Accepted Manuscript published: May 17, 2022 (version 1)
- Version of Record published: May 27, 2022 (version 2)
© 2022, Caveney et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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