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

  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},
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?

  • S. Frank
  • Biology, Chemistry
  • 2002
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.



Functional Mimicry of a Protein Hormone by a Peptide Agonist: The EPO Receptor Complex at 2.8 Å

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.

Activation and inhibition of erythropoietin receptor function: role of receptor dimerization

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.

Amino-terminal dimerization of an erythropoietin mimetic peptide results in increased erythropoietic activity.

Activation of the Erythropoietin (EPO) Receptor by Bivalent Anti-EPO Receptor Antibodies*

Mouse monoclonal antibodies raised to the soluble, extracellular domain of the human EPO receptor (EPOR) were found to be sufficient for both proliferation and differentiation of erythroid progenitor cells and that the constraints on dimerization necessary for activation are rather loose.

Homodimerization of erythropoietin receptor by a bivalent monoclonal antibody triggers cell proliferation and differentiation of erythroid precursors.

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.

Increased potency of an erythropoietin peptide mimetic through covalent dimerization

A chemically defined, dimeric form of an erythropoietin mimetic peptide (EMP) that displays 100-fold increased affinity for the EPOR and correspondingly elevated potency in cell-based assays and in mice is synthesized.

Ligand-induced activation of chimeric receptors between the erythropoietin receptor and receptor tyrosine kinases.

It is suggested that ligand-induced dimerization is a key step in activating the EPOR, and the interchangeability of domains between two distinct receptor families is demonstrated.

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.

Evidence for an accessory component that increases the affinity of the erythropoietin receptor.

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.