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

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, Andrew P. Leis, Jeffrey J. Babon () and Nadia J. Kershaw ()
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Kaiseal T. G. Sarson-Lawrence: Walter and Eliza Hall Institute of Medical Research
Joshua M. Hardy: Walter and Eliza Hall Institute of Medical Research
Josephine Iaria: Walter and Eliza Hall Institute of Medical Research
Dina Stockwell: Walter and Eliza Hall Institute of Medical Research
Kira Behrens: Walter and Eliza Hall Institute of Medical Research
Tamanna Saiyed: Walter and Eliza Hall Institute of Medical Research
Cyrus Tan: Walter and Eliza Hall Institute of Medical Research
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
Nicos A. Nicola: Walter and Eliza Hall Institute of Medical Research
Andrew P. Leis: Walter and Eliza Hall Institute of Medical Research
Jeffrey J. Babon: Walter and Eliza Hall Institute of Medical Research
Nadia J. Kershaw: Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45356-2

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