| Structural highlights
Disease
[I11RA_HUMAN] Craniosynostosis-dental anomalies. The disease is caused by mutations affecting the gene represented in this entry.
Function
[I11RA_HUMAN] Receptor for interleukin-11. The receptor systems for IL6, LIF, OSM, CNTF, IL11 and CT1 can utilize IL6ST for initiating signal transmission. The IL11/IL11RA/IL6ST complex may be involved in the control of proliferation and/or differentiation of skeletogenic progenitor or other mesenchymal cells. Essential for the normal development of craniofacial bones and teeth. Restricts suture fusion and tooth number.[1]
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[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nieminen P, Morgan NV, Fenwick AL, Parmanen S, Veistinen L, Mikkola ML, van der Spek PJ, Giraud A, Judd L, Arte S, Brueton LA, Wall SA, Mathijssen IM, Maher ER, Wilkie AO, Kreiborg S, Thesleff I. Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth. Am J Hum Genet. 2011 Jul 15;89(1):67-81. doi: 10.1016/j.ajhg.2011.05.024. PMID:21741611 doi:http://dx.doi.org/10.1016/j.ajhg.2011.05.024
- ↑ Metcalfe RD, Aizel K, Zlatic CO, Nguyen PM, Morton CJ, Lio DS, Cheng HC, Dobson RCJ, Parker MW, Gooley PR, Putoczki TL, Griffin MDW. The structure of the extracellular domains of human interleukin 11 alpha-receptor reveals mechanisms of cytokine engagement. J Biol Chem. 2020 Apr 24. pii: RA119.012351. doi: 10.1074/jbc.RA119.012351. PMID:32332100 doi:http://dx.doi.org/10.1074/jbc.RA119.012351
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