IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-45356-2.html
   My bibliography  Save this article

Cryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin

Author

Listed:
  • Kaiseal T. G. Sarson-Lawrence

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Joshua M. Hardy

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne
    Walter and Eliza Hall Institute of Medical Research)

  • Josephine Iaria

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Dina Stockwell

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Kira Behrens

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Tamanna Saiyed

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Cyrus Tan

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Leila Jebeli

    (University of Melbourne at the Peter Doherty Institute for Infection and Immunity)

  • Nichollas E. Scott

    (University of Melbourne at the Peter Doherty Institute for Infection and Immunity)

  • Toby A. Dite

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Nicos A. Nicola

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Andrew P. Leis

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne
    Walter and Eliza Hall Institute of Medical Research)

  • Jeffrey J. Babon

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Nadia J. Kershaw

    (Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

Abstract

Thrombopoietin (Tpo) is the primary regulator of megakaryocyte and platelet numbers and is required for haematopoetic stem cell maintenance. Tpo functions by binding its receptor (TpoR, a homodimeric Class I cytokine receptor) and initiating cell proliferation or differentiation. Here we characterise the murine Tpo:TpoR signalling complex biochemically and structurally, using cryo-electron microscopy. Tpo uses opposing surfaces to recruit two copies of receptor, forming a 1:2 complex. Although it binds to the same, membrane-distal site on both receptor chains, it does so with significantly different affinities and its highly glycosylated C-terminal domain is not required. In one receptor chain, a large insertion, unique to TpoR, forms a partially structured loop that contacts cytokine. Tpo binding induces the juxtaposition of the two receptor chains adjacent to the cell membrane. The therapeutic agent romiplostim also targets the cytokine-binding site and the characterisation presented here supports the future development of improved TpoR agonists.

Suggested Citation

  • Kaiseal T. G. Sarson-Lawrence & Joshua M. Hardy & Josephine Iaria & Dina Stockwell & Kira Behrens & Tamanna Saiyed & Cyrus Tan & Leila Jebeli & Nichollas E. Scott & Toby A. Dite & Nicos A. Nicola & An, 2024. "Cryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45356-2
    DOI: 10.1038/s41467-024-45356-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-45356-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-45356-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Rashid S. Syed & Scott W. Reid & Cuiwei Li & Janet C. Cheetham & Kenneth H. Aoki & Beishan Liu & Hangjun Zhan & Timothy D. Osslund & Arthur J. Chirino & Jiandong Zhang & Janet Finer-Moore & Steven Ell, 1998. "Efficiency of signalling through cytokine receptors depends critically on receptor orientation," Nature, Nature, vol. 395(6701), pages 511-516, October.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Julia Skokowa & Birte Hernandez Alvarez & Murray Coles & Malte Ritter & Masoud Nasri & Jérémy Haaf & Narges Aghaallaei & Yun Xu & Perihan Mir & Ann-Christin Krahl & Katherine W. Rogers & Kateryna Maks, 2022. "A topological refactoring design strategy yields highly stable granulopoietic proteins," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Xiaoning Wang & Yangyang Sun & Qian Wang & Fengying Liu & Weijie Yang & Xin Sui & Jun Yang & Minmin Zhang & Shuai Wang & Zhenyu Xiao & Yuan Luo & Yongan Wang & Tong Zhu, 2022. "Potential Common Mechanisms of Cytotoxicity Induced by Amide Herbicides via TRPA1 Channel Activation," IJERPH, MDPI, vol. 19(13), pages 1-18, June.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45356-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.