Biochemistry and Pharmacology - Research Publications

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Author: Parker, Michael × Author: Morton, Craig × Author: Nero, Tracy × Author: Broughton, Sophie ×

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    A dual role for the N-terminal domain of the IL-3 receptor in cell signalling
    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 (NATURE PUBLISHING GROUP, 2018-01-26)
    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.