Structural basis for EGFR ligand sequestration by Argos

The Drosophila protein Argos is an antagonist of epidermal growth factor receptor (EGFR) signalling that functions by binding and sequestering EGFR ligands. Here the structure of Argos bound to the EGFR ligand Spitz reveals that Argos engulfs the ligand using three related domains with structural resemblance to receptors for TGF-β and urokinase plasminogen activator. These results suggest that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues. In addition, the structures presented here define requirements for the design of artificial EGF-sequestering proteins that would be valuable anticancer therapeutics. Drosophila Argos is an antagonist of EGF receptor signalling that functions by binding and sequestering EGFR ligands. The structure of Argos bound to the EGFR ligand Spitz reveals that Argos engulfs the ligand using three related domains with structural resemblance to receptors for TGF-β and urokinase plasminogen activator. Members of the epidermal growth factor receptor (EGFR) or ErbB/HER family and their activating ligands are essential regulators of diverse developmental processes1,2. Inappropriate activation of these receptors is a key feature of many human cancers3, and its reversal is an important clinical goal. A natural secreted antagonist of EGFR signalling, called Argos, was identified in Drosophila4. We showed previously that Argos functions by directly binding (and sequestering) growth factor ligands that activate EGFR5. Here we describe the 1.6-A resolution crystal structure of Argos bound to an EGFR ligand. Contrary to expectations4,6, Argos contains no EGF-like domain. Instead, a trio of closely related domains (resembling a three-finger toxin fold7) form a clamp-like structure around the bound EGF ligand. Although structurally unrelated to the receptor, Argos mimics EGFR by using a bipartite binding surface to entrap EGF. The individual Argos domains share unexpected structural similarities with the extracellular ligand-binding regions of transforming growth factor-β family receptors8. The three-domain clamp of Argos also resembles the urokinase-type plasminogen activator (uPA) receptor, which uses a similar mechanism to engulf the EGF-like module of uPA9. Our results indicate that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues. In addition, the structures presented here define requirements for the design of artificial EGF-sequestering proteins that would be valuable anti-cancer therapeutics.