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

作者：Broughton Sophie E; Hercus Timothy R; Nero Tracy L; Kan Winnie L; Barry Emma F; Dottore Mara; Shing Karen S Cheung Tung; 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^*

来源：Nature Communications, 2018, 9(1): 386.

DOI：10.1038/s41467-017-02633-7

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.

• 出版日期2018-1-26
• 单位河北医科大学