Proteinaceous Metal-Binding Eph-Ephrin Tetramerization is Modulated by Copper and Chelators

EphrinB2 acts as a proteinaceous chelator that binds copper-like pockets on EphB1 and EphB2, snapping two low-affinity dimers into a high-affinity circular tetramer.

• Why it matters: Tetramerization is central to Eph–Ephrin activation, yet its mechanism is unclear, limiting how small molecules and metal chemistry might be used to modulate signaling.
• What they did: Using EphB–EphrinB2 dimers aligned to present two juxtaposed arginine-rich electropositive pockets, the study tests copper binding and inhibition by EDTA, EGTA, and 8-hydroxyquinoline.
• The result: Copper binding and competition by these chelators explain potent tetramer inhibition and reveal how small molecules, pH, salts, and copper dynamically modulate Eph–Ephrin binding kinetics for therapeutic targeting.

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