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

Author

Listed:
  • 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
    University of Melbourne)

  • 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
    University of Melbourne)

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.

Suggested Citation

  • 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. Wil, 2018. "A dual role for the N-terminal domain of the IL-3 receptor in cell signalling," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02633-7
    DOI: 10.1038/s41467-017-02633-7
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    Cited by:

    1. Timothy F. Shay & Seongmin Jang & Tyler J. Brittain & Xinhong Chen & Beth Walker & Claire Tebbutt & Yujie Fan & Damien A. Wolfe & Cynthia M. Arokiaraj & Erin E. Sullivan & Xiaozhe Ding & Ting-Yu Wang , 2024. "Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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