Title: A dual role for the N-terminal domain of the IL-3 receptor in cell signalling
Authors: Broughton, SE
Hercus, TR
Nero, TL
Kan, WL
Barry, EF
Dottore, M
Shing, KSCT
Morton, CJ
Dhagat, U
Hardy, MP
Wilson, NJ
Downton, MT
Schieber, C
Hughes, TP
Lopez, AF
Parker, MW
Issue Year: 2018
Series Nat. Commun.:
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 alpha-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 IL3R alpha 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 IL3R alpha 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.
URI: https://publications.svi.edu.au/publications/4644
Other Identifiers 10.1038/s41467-017-02633-7
Publication type Article