Journal article

The structure of the extracellular domains of human interleukin 11? receptor reveals mechanisms of cytokine engagement

Riley D Metcalfe, Kaheina Aizel, Courtney O Zlatic, Paul M Nguyen, Craig J Morton, Daisy Sio-Seng Lio, Heung-Chin Cheng, Renwick CJ Dobson, Michael W Parker, Paul R Gooley, Tracy L Putoczki, Michael DW Griffin

Journal of Biological Chemistry | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Published : 2020

Abstract

Interleukin (IL) 11 activates multiple intracellular signaling pathways by forming a complex with its cell surface α-receptor, IL-11Rα, and the β-subunit receptor, gp130. Dysregulated IL-11 signaling has been implicated in several diseases, including some cancers and fibrosis. Mutations in IL-11Rα that reduce signaling are also associated with hereditary cranial malformations. Here we present the first crystal structure of the extracellular domains of human IL-11Rα and a structure of human IL-11 that reveals previously unresolved detail. Disease-associated mutations in IL-11Rα are generally distal to putative ligand-binding sites. Molecular dynamics simulations showed that specific mutations..

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Grants

Awarded by National Health & Medical Research Council of Australia


Awarded by Australian Research Council


Awarded by Victorian Cancer Agency Fellowship


Awarded by Victorian Government Operational Infrastructure Support Scheme


Awarded by National Health & Medical Research Council of Australia Research Fellowship


Funding Acknowledgements

This work was supported by National Health & Medical Research Council of Australia Grants APP1147621 and APP1080498), Australian Research Council Future Fellowship Project FT140100544 (to M. D. W. G), Victorian Cancer Agency Fellowship MCRF16009 (to T. L. P.), National Health & Medical Research Council of Australia Research Fellowship APP1117183 (to M. W. P.), and Contract UOC1506 from the Victorian Government Operational Infrastructure Support Scheme to St. Vincent's Institute and the New Zealand Royal Society Marsden Fund (to R. C. J. D.).