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Publication Abstract from PubMed

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.

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 J Biol Chem. 2020 Apr 24. pii: RA119.012351. doi: 10.1074/jbc.RA119.012351. PMID:32332100^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.