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Orientation‐specific signalling by thrombopoietin receptor dimers
Author(s) -
Staerk Judith,
Defour JeanPhilippe,
Pecquet Christian,
Leroy Emilie,
AntoinePoirel Hélène,
Brett Ian,
Itaya Miki,
Smith Steven O,
Vainchenker William,
Constantinescu Stefan N
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.315
Subject(s) - biology , thrombopoietin , signalling , receptor , orientation (vector space) , microbiology and biotechnology , thrombopoietin receptor , computational biology , biochemistry , haematopoiesis , geometry , stem cell , mathematics
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.