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TitleStructure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis.
Journal, issue, pagesCell, Vol. 186, Issue 19, Page 4189-4203.e22, Year 2023
Publish dateSep 14, 2023
AuthorsNaotaka Tsutsumi / Zahra Masoumi / Sophie C James / Julie A Tucker / Hauke Winkelmann / William Grey / Lora K Picton / Lucie Moss / Steven C Wilson / Nathanael A Caveney / Kevin M Jude / Cornelius Gati / Jacob Piehler / Ian S Hitchcock / K Christopher Garcia /
PubMed AbstractThrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 Å resolution cryoelectron microscopy ...Thrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 Å resolution cryoelectron microscopy structure of the extracellular TPO-TPO receptor (TpoR or MPL) signaling complex, revealing the basis for homodimeric MPL activation and providing a structural rationalization for genetic loss-of-function thrombocytopenia mutations. The structure guided the engineering of TPO variants (TPO) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. Partial agonist TPO decoupled JAK/STAT from ERK/AKT/CREB activation, driving a bias for megakaryopoiesis and platelet production without causing significant HSC expansion in mice and showing superior maintenance of human HSCs in vitro. These data demonstrate the functional uncoupling of the two primary roles of TPO, highlighting the potential utility of TPO in hematology research and clinical HSC transplantation.
External linksCell / PubMed:37633268 / PubMed Central
MethodsEM (single particle)
Resolution3.4 Å
Structure data

29644

8g04

EMDB-29644, PDB-8g04:
Structure of signaling thrombopoietin-MPL receptor complex
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-MAN:
alpha-D-mannopyranose / Mannose

Source
  • homo sapiens (human)
KeywordsCYTOKINE / TPO / TpoR / receptor / signaling / haematology

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