The structure of the IL-11 signalling complex provides insight into receptor variants associated with craniosynostosis

Journal article


Sentosa, Darlene D., Metcalfe, Riley D., Sims, Natalie A., Putoczki, Tracy L. and Griffin, Michael D. W.. (2025). The structure of the IL-11 signalling complex provides insight into receptor variants associated with craniosynostosis. The FEBS Journal. 292(3), pp. 500-509. https://doi.org/10.1111/febs.17307
AuthorsSentosa, Darlene D., Metcalfe, Riley D., Sims, Natalie A., Putoczki, Tracy L. and Griffin, Michael D. W.
Abstract

Interleukin 11 (IL-11), a member of the IL-6 family of cytokines, has roles in haematopoiesis, inflammation, bone metabolism, and craniofacial development. IL-11 also has pathological roles in chronic inflammatory diseases, fibrosis, and cancer. In this structural snapshot, we explore our recently published cryo-EM structure of the human IL-11 signalling complex to understand the molecular mechanisms of complex formation and disease-associated mutations. IL-11 signals by binding to its cell surface receptors, the IL-11 receptor α subunit (IL-11Rα) and glycoprotein 130 (gp130), to form a hexameric signalling complex. We examine the locations within the complex of receptor sequence variants that are associated with craniosynostosis and craniosynostosis-like phenotypes and speculate on potential molecular mechanisms leading to defects in signalling function. While these causative amino acid sequence changes in IL-11Rα are generally distal to interfaces between components of the complex, important structural residues are highly represented, including proline residues, cysteine residues involved in disulfide bonds, and residues within or surrounding the tryptophan-arginine ladder. We also note the locations and potential effects of amino acid substitutions within the extracellular domains of gp130 that are associated with craniosynostosis. As focus on the physiological and pathological functions of IL-11 grows, the importance of high-resolution structural knowledge of IL-11 signalling to understand disease-associated mutations and to inform therapeutic strategies will only increase.

Keywordscraniosynostosis; cytokine signalling; IL11RA; IL6ST; interleukin 11; JAK/STAT pathway; signalling complex
Year2025
JournalThe FEBS Journal
Journal citation292 (3), pp. 500-509
PublisherWiley-Blackwell Publishing Ltd.
ISSN1742-4658
Digital Object Identifier (DOI)https://doi.org/10.1111/febs.17307
PubMed ID39462650
Scopus EID2-s2.0-85207786870
FunderNational Health and Medical Research Council (NHMRC)
Australian Research Council (ARC)
Sylvia and Charles Viertel Charitable Foundation
Publisher's version
License
All rights reserved
File Access Level
Controlled
Output statusPublished
Publication dates
Online27 Oct 2024
Publication process dates
Accepted15 Oct 2024
Deposited08 May 2025
ARC Funded ResearchThis output has been funded, wholly or partially, under the Australian Research Council Act 2001
Grant IDAPP1080498
APP1147621
DP230102422
Additional information

© 2024 Federation of European Biochemical Societies. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

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