A dual role for the N-terminal domain of the IL-3 receptor in cell signalling

  • Nat Commun. 2018 Jan 26;9(1):386. doi: 10.1038/s41467-017-02633-7.
Sophie E Broughton  1 ,  Timothy R Hercus  2 ,  Tracy L Nero  1 ,  Winnie L Kan  2 ,  Emma F Barry  2 ,  Mara Dottore  2 ,  Karen S Cheung Tung Shing  1  3 ,  Craig J Morton  1 ,  Urmi Dhagat  1 ,  Matthew P Hardy  4 ,  Nicholas J Wilson  4 ,  Matthew T Downton  5 ,  Christine Schieber  5 ,  Timothy P Hughes  6 ,  Angel F Lopez  7 ,  Michael W Parker  8  9
Affiliations
  • 1. Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.
  • 2. The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, 5000, Australia.
  • 3. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia.
  • 4. CSL Limited, Parkville, VIC, 3010, Australia.
  • 5. IBM Research Australia, Level 5, 204 Lygon Street, Carlton, VIC, 3053, Australia.
  • 6. South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, SA, 5000, Australia.
  • 7. The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, 5000, Australia. [email protected].
  • 8. Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia. [email protected].
  • 9. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia. [email protected].
PMID: 29374162 DOI: 10.1038/s41467-017-02633-7
Abstract

The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the α-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3Rα is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W. Mutagenesis, biochemical and functional studies show that the NTD of IL3Rα regulates IL-3 binding and signalling and reveal an unexpected role in preventing spontaneous receptor dimerisation. Our work identifies a dual role for the NTD in this cytokine receptor family, protecting against inappropriate signalling and dynamically regulating cytokine receptor binding and function.