An antagonist peptide–EPO receptor complex suggests that receptor dimerization is not sufficient for activation

@article{Livnah1998AnAP,
  title={An antagonist peptide–EPO receptor complex suggests that receptor dimerization is not sufficient for activation},
  author={Oded Livnah and Dana L. Johnson and Enrico A. Stura and Francis X. Farrell and Francis P. Barbone and Yun You and Kathleen D. Liu and Mark A. Goldsmith and Wen He and Christopher D. Krause and Sidney Pestka and Linda K. Jolliffe and Ian A. Wilson},
  journal={Nature Structural Biology},
  year={1998},
  volume={5},
  pages={993-1004}
}
Dimerization of the erythropoietin (EPO) receptor (EPOR), in the presence of either natural (EPO) or synthetic (EPO-mimetic peptides, EMPs) ligands is the principal extracellular event that leads to receptor activation. The crystal structure of the extracellular domain of EPOR bound to an inactive (antagonist) peptide at 2.7 Å resolution has unexpectedly revealed that dimerization still occurs, but the orientation between receptor molecules is altered relative to active (agonist) peptide… Expand
Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation.
TLDR
This model for a preformed dimer on the cell surface provides insights into the organization, activation, and plasticity of recognition of hematopoietic cell surface receptors. Expand
Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain
TLDR
A model in which TM domain-induced dimerization maintains unliganded EpoR in an inactive state that can readily be switched to an active state by physiologic levels of Epo is proposed. Expand
Mechanism of erythropoietin receptor activation
Erythropoietin receptor (EPOR) is a founding member of the cytokine receptor superfamily [1]. A type I transmembrane protein that binds the ligand erythropoietin (EPO) with high affinity (kDaExpand
Self assembly of the transmembrane domain promotes signal transduction through the erythropoietin receptor
TLDR
It is shown that the EpoR transmembrane domain (TM) has a strong potential to self interact in a bacterial reporter system and abrogates formation of disulfide-linked receptor homodimers and consequently results in the loss of ligand-independent signal transduction. Expand
Activation of Erythropoietin Receptor through a Novel Extracellular Binding Site.
TLDR
The extracellular binding site for ERP is now characterized and it is speculated that ERP binds to its identical sequence on EPOR, as ERP self-interacts. Expand
Oligomerization and Scaffolding Functions of the Erythropoietin Receptor Cytoplasmic Tail*
TLDR
Key relationships involved in the assembly and activation of the EPOR signal transduction complex are defined which may be applicable to other homodimeric cytokine receptors. Expand
A diversity of antibody epitopes can induce signaling through the erythropoietin receptor.
TLDR
The binding epitopes of a panel of eight agonistic, single-chain antibody (scFv-Fc) constructs were determined and it was found that while some of these constructs bound to receptor epitopes shared by the ligand, others bound in completely unique ways. Expand
Active and inactive orientations of the transmembrane and cytosolic domains of the erythropoietin receptor dimer.
TLDR
A specific EpoR-activated interface is proposed and suggested for structural and signaling studies and one dimeric TM conformation is identified that imparts full activity to the cytosolic domain of the receptor and signals via JAK2, STAT proteins, and MAP kinase. Expand
Minireview: Receptor Dimerization in GH and Erythropoietin Action-It Takes Two to Tango, But How?
  • S. Frank
  • Medicine, Biology
  • Endocrinology
  • 2002
TLDR
There is good evidence that the unliganded receptor is already a preformed dimer that is activated by a ligand-induced change in the receptor conformation for EpoR, and in some measure to the unavailability of the analogous crystal structure of theunliganded GHR extracellular domain. Expand
Evaluating energetics of erythropoietin ligand binding to homodimerized receptor extracellular domains.
TLDR
AUC established an assembly model and provided a foundation on which SPR, ITC, and CD studies could be based and from which interpretation of these data could be extended, as well as demonstrating that the EPOR-Fc is a valid model for the dimerized receptor on the cell surface. Expand
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TLDR
The crystal structure of a complex of this agonist peptide with the extracellular domain of EPO receptor reveals that a peptide dimer induces an almost perfect twofold dimerization of the receptor, and suggests the design of nonpeptidic small molecule mimetics for EPO and other cytokines may indeed be achievable. Expand
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TLDR
The hypothesis that an initial step in EPO- andEPO-R-mediated signal transduction is ligand-induced receptor dimerization is strengthened by coexpressed mutants of the receptor missing all or part of the cytosolic domain. Expand
Amino-terminal dimerization of an erythropoietin mimetic peptide results in increased erythropoietic activity.
TLDR
The potency of previously isolated peptides that are modest agonists of the EPO receptor was dramatically increased by PEG-induced dimerization, and the conversion of an inactive peptide into an agonist further supports the idea thatDimerization can mediate receptor activation. Expand
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TLDR
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TLDR
The data indeed demonstrate that EPO and MoAb34 antagonize ligand-dependent cell proliferation with IC50 values of approximately 20 and 2 mumol/L, respectively, and the data for proliferation and differentiation activity were consistent with the receptor dimer formation on the cell surface predicted by the model. Expand
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TLDR
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TLDR
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TLDR
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TLDR
Support for the hypothesis that there was a constitutively expressed cellular component in CHO cells that can increase Epo receptor affinity was provided by the finding that fusion of IW 201 cells with nontransfected CHO cells resulted in high affinity binding sites for Epo. Expand
Efficiency of signalling through cytokine receptors depends critically on receptor orientation
TLDR
The crystal structure of erythropoietin complexed to the extracellular ligand-binding domains of the erymorphic receptor, determined at 1.9 Å from two crystal forms, shows that erythrooiet in imposes a unique 120° angular relationship and orientation that is responsible for optimal signalling through intracellular kinase pathways. Expand
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