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

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

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.

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