Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis.

ABSTRACT: 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^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 show

SUBMITTER: Tsutsumi N 

PROVIDER: S-EPMC10528194 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature