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- Title
A dual role for the N-terminal domain of the IL-3 receptor in cell signalling.
- Authors
Broughton, Sophie E.; Hercus, Timothy R.; Nero, Tracy L.; Kan, Winnie L.; Barry, Emma F.; Dottore, Mara; Cheung Tung Shing, Karen S.; Morton, Craig J.; Dhagat, Urmi; Hardy, Matthew P.; Wilson, Nicholas J.; Downton, Matthew T.; Schieber, Christine; Hughes, Timothy P.; Lopez, Angel F.; Parker, Michael W.
- 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.
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-017-02633-7