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

Metcalfe, RD; Aizel, K; Zlatic, CO; Nguyen, PM; Morton, CJ; Lio, DS; Cheng, HC; Dobson, RCJ; Parker, MW; Gooley, PR; Putoczki, TL; Griffin, MDW

Author(s): Metcalfe, RD; Aizel, K; Zlatic, CO; Nguyen, PM; Morton, CJ; Lio, DS; Cheng, HC; Dobson, RCJ; Parker, MW; Gooley, PR; Putoczki, TL; Griffin, MDW;
Details: Publication Year 2020-04-24,Volume 295,Issue #24,Page 8285-8301
Journal Title: Journal of Biological Chemistry
Abstract: Interleukin 11 (IL-11) activates multiple intracellular signalling pathways by forming a complex with its cell surface alpha-receptor, IL-11Ralpha, and the beta-subunit receptor, gp130. Dysregulated IL-11 signalling has been implicated in several diseases, including some cancers and fibrosis. Mutations in IL-11Ralpha that reduce signalling are also associated with hereditary cranial malformations. Here we present the first crystal structure of the extracellular domains of human IL-11Ralpha, and a structure of human IL-11 that reveals previously unresolved detail. Disease-associated mutations in IL-11Ralpha are generally distal to putative ligand binding sites. Molecular dynamics simulations showed that specific mutations destabilise IL-11Ralpha and may have indirect effects on the cytokine binding region. We show that IL-11 and IL-11Ralpha form a 1:1 complex with nanomolar affinity and present a model of the complex. Our results suggest that the thermodynamic and structural mechanisms of complex formation between IL-11 and IL-11Ralpha differ substantially from those previously reported for similar cytokines. This work reveals key determinants of the engagement of IL-11 by IL-11Ralpha that may be exploited in the development of strategies to modulate formation of the IL-11/IL-11Ralpha complex.
Publisher: ASBMB
Research Division(s): Personalised Oncology
PubMed ID: 32332100
Publisher's Version: https://doi.org/10.1074/jbc.RA119.012351
Open Access at Publisher's Site: https://doi.org/10.1074/jbc.RA119.012351
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2020-05-04 10:30:34

Last Modified: 2025-04-11 10:34:09