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Structure of the IL-27 quaternary receptor signaling complex
Open accessPreprint — published as 10.7554/elife.78463
Abstract
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 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 (cryo-EM) to determine the quaternary structure of IL-27 (p28/Ebi3) bound to receptor subunits, 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.
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Metadata
- Authors
- Caveney, N. A., Glassman, C. R., Jude, K. M., Tsutsumi, N., & Garcia, K. C.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Venue
- eLife
- Publisher
- openRxiv
- Published
- 2022-03-08
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9142143
- OpenAlex
- W4280521018
- Cited by
- 43
- References
- 1
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 13 · 2023: 10 · 2022: 4
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute
- G. Harold and Leila Y. Mathers Foundation
- National Institutes of Health
- Canadian Institutes of Health Research
- Japan Society for the Promotion of Science (22K20632)
- National Institute of Allergy and Infectious Diseases (R37AI051321, R01AI051321)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- IL-27, gp130, EBI3, IL-12 family cytokines, interleukin-6, IL-12, IL-23, STAT1, STAT3, Janus kinase, cytokine structure
- MeSH terms
- Humans, Receptors, Interleukin, Interleukin-12, Protein Structure, Quaternary, Cytokine Receptor gp130, Interleukin-27
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