Crystallographic Evidence for Preformed Dimers of Erythropoietin Receptor Before Ligand Activation

Science  12 Feb 1999:
Vol. 283, Issue 5404, pp. 987-990
DOI: 10.1126/science.283.5404.987

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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.

  • * Present address: Department of Biological Chemistry, Institute of Life Sciences, Wolfson Centre for applied Structural Biology, Hebrew University of Jerusalem, Jerusalem 91904, Israel.

  • Present address: Department d'Ingenierie et d'Etude des Proteines, BAT 152 C.E.A./SACLAY, 91191 Gif sur Yvette Cedex, France.

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