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Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant

Author

Listed:
  • Riley D. Metcalfe

    (University of Melbourne, Parkville
    National Cancer Institute, Frederick)

  • Eric Hanssen

    (University of Melbourne, Parkville
    University of Melbourne, Parkville
    University of Melbourne, Parkville)

  • Ka Yee Fung

    (Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne, Parkville)

  • Kaheina Aizel

    (University of Melbourne, Parkville
    Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne, Parkville)

  • Clara C. Kosasih

    (University of Melbourne, Parkville
    Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne, Parkville)

  • Courtney O. Zlatic

    (University of Melbourne, Parkville)

  • Larissa Doughty

    (University of Melbourne, Parkville)

  • Craig J. Morton

    (University of Melbourne, Parkville
    CSIRO Biomedical Manufacturing Program, Clayton)

  • Andrew P. Leis

    (University of Melbourne, Parkville
    Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne, Parkville)

  • Michael W. Parker

    (University of Melbourne, Parkville
    University of Melbourne, Parkville
    St Vincent’s Institute of Medical Research, Fitzroy)

  • Paul R. Gooley

    (University of Melbourne, Parkville)

  • Tracy L. Putoczki

    (Walter and Eliza Hall Institute of Medical Research, Parkville
    University of Melbourne, Parkville)

  • Michael D. W. Griffin

    (University of Melbourne, Parkville
    University of Melbourne, Parkville)

Abstract

Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family β-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.

Suggested Citation

  • Riley D. Metcalfe & Eric Hanssen & Ka Yee Fung & Kaheina Aizel & Clara C. Kosasih & Courtney O. Zlatic & Larissa Doughty & Craig J. Morton & Andrew P. Leis & Michael W. Parker & Paul R. Gooley & Tracy, 2023. "Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42754-w
    DOI: 10.1038/s41467-023-42754-w
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    References listed on IDEAS

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    1. Shikha Nayar & Joshua K. Morrison & Mamta Giri & Kyle Gettler & Ling-shiang Chuang & Laura A. Walker & Huaibin M. Ko & Ephraim Kenigsberg & Subra Kugathasan & Miriam Merad & Jaime Chu & Judy H. Cho, 2021. "A myeloid–stromal niche and gp130 rescue in NOD2-driven Crohn’s disease," Nature, Nature, vol. 593(7858), pages 275-281, May.
    2. Sebastian Schafer & Sivakumar Viswanathan & Anissa A. Widjaja & Wei-Wen Lim & Aida Moreno-Moral & Daniel M. DeLaughter & Benjamin Ng & Giannino Patone & Kingsley Chow & Ester Khin & Jessie Tan & Sonia, 2017. "IL-11 is a crucial determinant of cardiovascular fibrosis," Nature, Nature, vol. 552(7683), pages 110-115, December.
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    1. Scott Gardner & Yibo Jin & Paul K. Fyfe & Tomas B. Voisin & Junel Sotolongo Bellón & Elizabeth Pohler & Jacob Piehler & Ignacio Moraga & Doryen Bubeck, 2024. "Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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