Crystallographic Evidence for Preformed Dimers of Erythropoietin Receptor Before Ligand Activation

Abstract

Erythropoietin receptor (EPOR) is thought to be activated by ligand-induced homodimerization. However, structures of agonist and antagonist peptide complexes of EPOR, as well as an EPO-EPOR complex, have shown that the actual dimer configuration is critical for the biological response and signal efficiency. The crystal structure of the extracellular domain of EPOR in its unliganded form at 2.4 angstrom resolution has revealed a dimer in which the individual membrane-spanning and intracellular domains would be too far apart to permit phosphorylation by JAK2. This unliganded EPOR dimer is formed from self-association of the same key binding site residues that interact with EPO-mimetic peptide and EPO ligands. 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.

Erythropoietin as an antiapoptotic, tissue-protective cytokine

“…21,22 One possible signal transduction pathway involved in the antiapoptotic action of EPO in erythroid cells is outlined in Figure 1, based on the known signal transduction pathways activated by EPO (excellently reviewed in Wojchowski et al 23 ). Binding of EPO to the extracellular domain of preformed EPOR dimers 24 initiates signaling that in turn results in recruitment and activation of Janus kinase 2 (JAK2) by the intracellular domain of EPOR. JAK2 then phosphorylates several proteins including STAT5.…”

Erythropoietin and erythropoietin receptor expression in human prostate cancer

“…[4][5][6] The interaction of erythropoietin with its cell surface receptor induces a conformational change of receptor homodimers leading to the activation of intracellular signal transduction that mediates the ability of erythropoietin to support the proliferation, terminal differentiation and survival of erythroid cells. 7,8 Several previous studies have provided evidence for the presence of a functional erythropoietinerythropoietin receptor system in nonhematopoietic cell types and organs. For instance, the expression of erythropoietin receptor in vascular endothelial cells and neurons is associated with diverse physiological effects of erythropoietin that are distinct from its regulatory function in erythropoiesis.…”

Cytokine receptors and hematopoietic differentiation

“…The cytokines bind to their receptors with high picomolar affinity. This event triggers receptor homodimerization (for example G-CSFR; Horan et al, 1996;Tamada et al, 2006) or heterodimerization/ oligomerization of receptor subunits (for example GM-CSFR; Hayashida et al, 1990) or induces a conformational change in preformed receptor dimers (EPOR; Livnah et al, 1999;Constantinescu et al, 2001) resulting in the activation of the Janus kinases (JAKs). These tyrosine kinases are constitutively associated with cytokine receptors with binding mediated by interactions between the FERM domain of JAK and the Box1 membrane proximal intracytoplasmic region of the receptor.…”