Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation

Erythropoietin receptor (EPOR) is thought to be activated by Ligand-induced homodimerization. However, structures of agonist and antagonist peptide co mplexes of EPOR, as well as an EPO-EPOR complex, have shown that the actual dimer configuration is critical for the biological response and signal eff iciency. The crystal structure of the extracellular domain of EPOR in its u nliganded form at 2.4 angstrom resolution has revealed a dimer in which the individual membrane-spanning and intracellular domains would be too far ap art 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, an d plasticity of recognition of hematopoietic cell surface receptors.