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TitleCryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 1135, Year 2024
Publish dateFeb 7, 2024
AuthorsKaiseal 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 / Nadia J Kershaw /
PubMed AbstractThrombopoietin (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 ...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.
External linksNat Commun / PubMed:38326297 / PubMed Central
MethodsEM (single particle)
Resolution3.6 Å
Structure data

EMDB-41805, PDB-8u18:
Cryo-EM structure of murine Thrombopoietin receptor ectodomain in complex with Tpo
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-MAN:
alpha-D-mannopyranose

Source
  • mus musculus (house mouse)
  • saccharomyces cerevisiae (brewer's yeast)
KeywordsCYTOKINE/RECEPTOR / Receptor / cytokine / signalling / haematopoiesis / CYTOKINE-RECEPTOR complex

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