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… 

Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation.

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.

Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain

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.

Mechanism of erythropoietin receptor activation

Erythropoietin receptor is a founding member of the cytokine receptor superfamily and is considered a simple receptor, unlike other superfamily members, like the receptors for interleukin (IL)-6 type cytokines or for granulocyte colony-stimulating factor (G-CSF), which possess other extracellular sequences, such as immunoglobulin-like domains.

Activation of erythropoietin receptor through a novel extracellular binding site.

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.

Activation of Erythropoietin Receptor through a Novel Extracellular Binding Site.

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.

Oligomerization and Scaffolding Functions of the Erythropoietin Receptor Cytoplasmic Tail*

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.

A diversity of antibody epitopes can induce signaling through the erythropoietin receptor.

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.

Minireview: Receptor Dimerization in GH and Erythropoietin Action-It Takes Two to Tango, But How?

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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.
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Small Peptides as Potent Mimetics of the Protein Hormone Erythropoietin

Random phage display peptide libraries and affinity selective methods were used to isolate small peptides that bind to and activate the receptor for the cytokine erythropoietin (EPO) and these peptides appear to be identical to those induced by the natural ligand.

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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.