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

Sophie E. Broughton, Timothy R. Hercus, Tracy L. Nero, Winnie L. Kan, Emma F. Barry, Mara Dottore, Karen S. Cheung Tung Shing, Craig J. Morton, Urmi Dhagat, Matthew P. Hardy, Nicholas J. Wilson, Matthew T. Downton, Christine Schieber, Timothy Hughes, Angel F. Lopez, Michael W. Parker

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Article number386
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished or Issued - 1 Jan 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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