Structure of the Thrombopoietin-MPL Receptor Complex is a Blueprint for Biasing Hematopoiesis

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Aug 26

PMID 37633268

Authors

Naotaka 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

Affiliations

Soon will be listed here.

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) 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.

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