Journal article
A dual role for the N-terminal domain of the IL-3 receptor in cell signalling
SE Broughton, TR Hercus, TL Nero, WL Kan, EF Barry, M Dottore, KS Cheung Tung Shing, CJ Morton, U Dhagat, MP Hardy, NJ Wilson, MT Downton, C Schieber, TP Hughes, AF Lopez, MW Parker
Nature Communications | NATURE PUBLISHING GROUP | Published : 2018
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 ..
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Awarded by Leukaemia Foundation
Funding Acknowledgements
This research was partly undertaken on the MX2 beamline at the Australian Synchrotron, Victoria, Australia and we thank the beamline staff for their assistance. We thank Anna Sapa for technical assistance, Denis Tvorogov for the HEK293-T cells expressing beta c, Hayley Ramshaw for the TF-1Hi cell line, Paul Ekert (Murdoch Children's Research Institute) for the HoxA9 expression construct, Tony Cambareri for the 1B5 hybridoma and Joanna Woodcock for helpful discussions. We acknowledge the use of the CSIRO Collaborative Crystallisation Centre (C3), Melbourne, Australia for our initial crystallisation studies, and the SA Pathology Detmold Family Cytometry Centre for use of flow cytometry facilities. This research was supported by a Victorian Life Sciences Computation Initiative (VLSCI) grant number RA0002 on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia. This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC) to T.R.H., U.D., M.W.P. and A.F.L., Cure Cancer Australia to S.E.B., Cancer Council SA Beat Cancer Fund to T.P.H. and from the Australian Cancer Research Foundation to M.W.P. Funding from the Victorian Government Operational Infrastructure Support Scheme to St Vincent's Institute is acknowledged. S.E.B is a Postdoctoral Fellow supported by the Leukaemia Foundation. T.P.H. is an NHMRC Practitioner Fellow and M.W.P. is an NHMRC Research Fellow.