Orientation-specific Signalling by Thrombopoietin Receptor Dimers

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2011 Sep 6

PMID 21892137

Citations 38

Authors

Judith Staerk

Jean-Philippe Defour

Christian Pecquet

Emilie Leroy

Helene Antoine-Poirel

Ian Brett

Miki Itaya

Steven O Smith

William Vainchenker

Stefan N Constantinescu

Affiliations

Soon will be listed here.

Abstract

Ligand binding to the thrombopoietin receptor is thought to stabilize an active receptor dimer that regulates megakaryocyte differentiation and platelet formation, as well as haematopoietic stem cell renewal. By fusing a dimeric coiled coil in all seven possible orientations to the thrombopoietin receptor transmembrane (TM)-cytoplasmic domains, we show that specific biological effects and in vivo phenotypes are imparted by distinct dimeric orientations, which can be visualized by cysteine mutagenesis and crosslinking. Using functional assays and computational searches, we identify one orientation that represents the inactive dimeric state and another similar to a physiologically activated receptor. Several other dimeric orientations are identified that induce proliferation and in vivo myeloproliferative and myelodysplastic disorders, indicating the receptor can signal from several dimeric interfaces. The set of dimeric thrombopoietin receptors with different TM orientations may offer new insights into the activation of distinct signalling pathways by a single receptor and suggests that subtle differences in cytokine receptor dimerization provide a new layer of signalling regulation that is relevant for disease.

Citing Articles

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Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer.

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Defour J, Leroy E, Dass S, Balligand T, Levy G, Brett I Elife. 2023; 12.

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