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 destabilize IL-11Rα and may have indirect effects on the cytokine-binding region. We show that IL-11 and IL-11Rα 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-11Rα differ substantially from those previously reported for similar cytokines. This work reveals key determinants of the engagement of IL-11 by IL-11Rα that may be exploited in the development of strategies to modulate formation of the IL-11-IL-11Rα complex.
Highlights
Interleukin (IL) 11 activates multiple intracellular signaling pathways by forming a complex with its cell surface ␣-receptor, IL-11R␣, and the -subunit receptor, gp130
We present a model of the Interleukin 11 (IL-11)–IL-11R␣ complex and in combination with biophysical and mutagenic characterization of the cytokine–receptor interaction show that IL-11R␣ and IL-6R␣ engage their cognate cytokines with similar affinities but use surprisingly different thermodynamic and structural mechanisms
Initial phase estimates were obtained by molecular replacement using domains from unpublished Fab-bound structures of IL-11R␣, and the structure was refined at a resolution of 3.43 Å (PDB code 6O4P)
Summary
The structure of the extracellular domains of human interleukin 11␣ receptor reveals mechanisms of cytokine engagement. From the 1Department of Biochemistry and Molecular Biology, Bio Molecular Science and Biotechnology Institute and the 7Department of Medical Biology and Department of Surgery, University of Melbourne, Parkville, Victoria, Australia, the 2Inflammation, 3Personalised Oncology, and 4Structural Biology Divisions, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, the 5Biomolecular Interaction Centre and School of Biological Sciences, University of Canterbury, Christchurch, New Zealand, and the 6Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
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