8g04
From Proteopedia
Structure of signaling thrombopoietin-MPL receptor complex
Structural highlights
DiseaseTPO_HUMAN Defects in THPO are the cause of thrombocythemia type 1 (THCYT1) [MIM:187950. A myeloproliferative disorder characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications.[1] FunctionTPO_HUMAN Lineage-specific cytokine affecting the proliferation and maturation of megakaryocytes from their committed progenitor cells. It acts at a late stage of megakaryocyte development. It may be the major physiological regulator of circulating platelets. Publication Abstract from PubMedThrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 A 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(mod)) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. Partial agonist TPO(mod) 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(mod) in hematology research and clinical HSC transplantation. Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis.,Tsutsumi N, Masoumi Z, James SC, Tucker JA, Winkelmann H, Grey W, Picton LK, Moss L, Wilson SC, Caveney NA, Jude KM, Gati C, Piehler J, Hitchcock IS, Garcia KC Cell. 2023 Sep 14;186(19):4189-4203.e22. doi: 10.1016/j.cell.2023.07.037. Epub , 2023 Aug 25. PMID:37633268[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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