title: 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.
authors.affiliation: Department of Molecular Biology and Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: O
authors.initials: O
authors.lastname: Livnah
authors.forename: E A
authors.initials: EA
authors.lastname: Stura
authors.forename: S A
authors.initials: SA
authors.lastname: Middleton
authors.forename: D L
authors.initials: DL
authors.lastname: Johnson
authors.forename: L K
authors.initials: LK
authors.lastname: Jolliffe
authors.forename: I A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D002462:Cell Membrane / Q000737:chemistry; D018360:Crystallography, X-Ray; D019281:Dimerization; D004921:Erythropoietin / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D053614:Janus Kinase 2; D008024:Ligands; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000378:metabolism; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin / Q000737:chemistry* / Q000378:metabolism