Crystal structure of the ligand-binding domain of the promiscuous EphA4 receptor reveals two distinct conformations

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 2.3 Å 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.

Research highlights
► Crystal structure of the ligand-binding domain of the promiscuous EphA4 receptor reveals two distinct conformations (Singla et al.)
► EphA4 receptor has two distinct conformations in the unbound state
► Conformational plasticity of EphA4 centers around two flexible ligand-binding loops
► Loop-flexibility is retained also in the ligand-bound forms of EphA4
► Unusual conformational flexibility makes EphA4 able to bind all ephrin ligands.