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

Sarson-Lawrence, KTG; Hardy, JM; Iaria, J; Stockwell, D; Behrens, K; Saiyed, T; Tan, C; Jebeli, L; Scott, NE; Dite, TA; Nicola, NA; Leis, AP; Babon, JJ; Kershaw, NJ

Author(s): Sarson-Lawrence, KTG; Hardy, JM; Iaria, J; Stockwell, D; Behrens, K; Saiyed, T; Tan, C; Jebeli, L; Scott, NE; Dite, TA; Nicola, NA; Leis, AP; Babon, JJ; Kershaw, NJ;
Details: Publication Year 2024-02-07,Volume 15,Issue #1,Page 1135
Journal Title: Nature Communications
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.
Publisher: Springer Nature
Keywords: Mice; Animals; *Receptors, Thrombopoietin/metabolism; Cryoelectron Microscopy; *Thrombopoietin; Receptors, Cytokine/metabolism; Signal Transduction
Research Division(s): Chemical Biology; Advanced Technology And Biology; Personalised Oncology; Structural Biology
PubMed ID: 38326297
Publisher's Version: https://doi.org/10.1038/s41467-024-45356-2
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-024-45356-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-02-29 09:02:01

Last Modified: 2024-02-29 09:13:31