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

Nat Commun. 2018 Jan 26;9(1):386. doi: 10.1038/s41467-017-02633-7.

Sophie E Broughton ¹, Timothy R Hercus ², Tracy L Nero ¹, Winnie L Kan ², Emma F Barry ², Mara Dottore ², Karen S Cheung Tung Shing ¹ ³, Craig J Morton ¹, Urmi Dhagat ¹, Matthew P Hardy ⁴, Nicholas J Wilson ⁴, Matthew T Downton ⁵, Christine Schieber ⁵, Timothy P Hughes ⁶, Angel F Lopez ⁷, Michael W Parker ⁸ ⁹

Affiliations

1 Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.
2 The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, 5000, Australia.
3 Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia.
4 CSL Limited, Parkville, VIC, 3010, Australia.
5 IBM Research Australia, Level 5, 204 Lygon Street, Carlton, VIC, 3053, Australia.
6 South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, SA, 5000, Australia.
7 The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, 5000, Australia. angel.lopez@sa.gov.au.
8 Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia. mparker@svi.edu.au.
9 Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia. mparker@svi.edu.au.

PMID: 29374162 DOI: 10.1038/s41467-017-02633-7

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.

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