期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 24, 页码 8285-8301出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.012351
关键词
cytokine; receptor structure-function; interleukin; signaling; structural biology; inflammation; cancer; fibrosis; gp130; IL6 family cytokine
资金
- National Health & Medical Research Council of Australia [APP1147621, APP1080498]
- Australian Research Council [FT140100544]
- Victorian Cancer Agency Fellowship [MCRF16009]
- Victorian Government Operational Infrastructure Support Scheme [UOC1506]
- New Zealand Royal Society Marsden Fund
- National Health & Medical Research Council of Australia Research Fellowship [APP1117183]
- Australian Research Council [FT140100544] Funding Source: Australian Research Council
Interleukin (IL) 11 activates multiple intracellular signaling pathways by forming a complex with its cell surface ?-receptor, IL-11R?, and the ?-subunit receptor, gp130. Dysregulated IL-11 signaling has been implicated in several diseases, including some cancers and fibrosis. Mutations in IL-11R? that reduce signaling are also associated with hereditary cranial malformations. Here we present the first crystal structure of the extracellular domains of human IL-11R? and a structure of human IL-11 that reveals previously unresolved detail. Disease-associated mutations in IL-11R? are generally distal to putative ligand-binding sites. Molecular dynamics simulations showed that specific mutations destabilize IL-11R? and may have indirect effects on the cytokine-binding region. We show that IL-11 and IL-11R? 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-11R? differ substantially from those previously reported for similar cytokines. This work reveals key determinants of the engagement of IL-11 by IL-11R? that may be exploited in the development of strategies to modulate formation of the IL-11?IL-11R? complex.
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