title: Crystal structure of the ligand-binding domain of the promiscuous EphA4 receptor reveals two distinct conformations.
abstract: Eph receptors and their ephrin ligands are important mediators of cell-cell communication. They are divided in two subclasses based on their affinities for each other and on sequence conservation. Receptor-ligand binding within each subclass is fairly promiscuous, while binding cross the subclasses happens rarely. EphA4 is an exception to this general rule, since it has long been known to bind both A- and B-class ephrin ligands but the reason for this exceptional behavior has not been worked out at molecular level. Recent structural and biochemical studies on EphA4 ligand-binding domain alone and in complex with its ligands have addressed this question. However, the published structures of EphA4/ephrin complexes differ considerably from each other and strikingly different explanations for the exceptional promiscuity of EphA4 were proposed. To address these contradictory findings, we have determined a crystal structure of the EphA4 ligand-binding domain at 2.3A resolution and show that the receptor has an unprecedented ability to exist in two very different, well-ordered conformations even in the unbound state. Our results suggest that the ligand promiscuity of the Ephs is directly correlated with the structural flexibility of the ligand-binding surface of the receptor.
authors.affiliation: Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Singla
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Goldgur
authors.forename: Kai
authors.initials: K
authors.lastname: Xu
authors.forename: Sari
authors.initials: S
authors.lastname: Paavilainen
authors.forename: Dimitar B
authors.initials: DB
authors.lastname: Nikolov
authors.forename: Juha P
authors.initials: JP
authors.lastname: Himanen
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D017434:Protein Structure, Tertiary; D036122:Receptor, EphA4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D036122:Receptor, EphA4