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 P. Hughes, Angel F. Lopez () and Michael W. Parker ()
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Sophie E. Broughton: St. Vincent’s Institute of Medical Research
Timothy R. Hercus: SA Pathology and the University of South Australia
Tracy L. Nero: St. Vincent’s Institute of Medical Research
Winnie L. Kan: SA Pathology and the University of South Australia
Emma F. Barry: SA Pathology and the University of South Australia
Mara Dottore: SA Pathology and the University of South Australia
Karen S. Cheung Tung Shing: St. Vincent’s Institute of Medical Research
Craig J. Morton: St. Vincent’s Institute of Medical Research
Urmi Dhagat: St. Vincent’s Institute of Medical Research
Matthew P. Hardy: CSL Limited
Nicholas J. Wilson: CSL Limited
Matthew T. Downton: IBM Research Australia
Christine Schieber: IBM Research Australia
Timothy P. Hughes: South Australian Health and Medical Research Institute and University of Adelaide
Angel F. Lopez: SA Pathology and the University of South Australia
Michael W. Parker: St. Vincent’s Institute of Medical Research

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02633-7

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