Journal article
Cryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin
Kaiseal TG 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, Nadia J Kershaw
Nature Communications | Nature Portfolio | Published : 2024
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 cha..
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Grants
Awarded by Medical Research Future Fund (MRFF)
Awarded by NHMRC Investigator Grant
Awarded by Australian Research Council Future Fellowship
Awarded by Australian Research Council
Awarded by National Health and Medical Research Council
Funding Acknowledgements
We thank the staff at the Ian Holmes Imaging Centre, Bio21 Institute, for access to and assistance with the Titan Krios microscope used for data collection. This research was undertaken with the assistance of Milton HPC/Virtual Machines, supported by WEHI. This work was supported by philanthropic donations through the WEHI accelerator fund and via a Medical Research Future Fund (MRFF) grant MRF2008972. K.S.L. was supported by a Walter and Eliza Hall Handman PhD scholarship, J.M.H. is supported by an NHMRC Investigator Grant (2008096) and is a member of the Australian Research Council Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery (IC200100052). N.E.S. is supported by an Australian Research Council Future Fellowship (FT200100270), an Australian Research Council Discovery Project Grant (DP210100362) and a National Health and Medical Research Council Ideas Grant (2018980). We thank the Melbourne Mass Spectrometry and Proteomics Facility of the Bio21 Molecular Science and Biotechnology Institute for access to MS instrumentation. The contents of this published material are solely the responsibility of the individual authors and do not reflect the views of the NHMRC or funding partners.