Thrombopoietin receptor activation: transmembrane helix dimerization, rotation, and allosteric modulation.

ABSTRACT: We report how rotational variations in transmembrane (TM) helix interactions participate in the activity states of the thrombopoietin receptor (TpoR), a type 1 cytokine receptor that controls the production of blood platelets. We also explore the mechanism of small-molecule agonists that do not mimic the natural ligand. We show, by a combination of cysteine cross-linking, alanine-scanning mutagenesis, and computational simulations, that the TpoR TM dimerizes strongly and can adopt 3 different stable, rotationally related conformations, which may correspond to specific states of the full-length receptor (active, inactive, and partially active). Thus, our data suggest that signaling and inactive states of the receptor are related by receptor subunit rotations, rather than a simple monomer-di

SUBMITTER: Matthews EE 

PROVIDER: S-EPMC3114528 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature