Structural basis for EGFR ligand sequestration by Argos

Abstract

Members of the epidermal growth factor receptor (EGFR) or ErbB/HER family and their activating ligands are essential regulators of diverse developmental processes. Inappropriate activation of these receptors is a key feature of many human cancers, and its reversal is an important clinical goal. A natural secreted antagonist of EGFR signaling, called Argos, was identified in Drosophila. Argos functions by directly binding to (and sequestering) growth factor ligands that activate EGFR. Here we describe the 1.6Å‐resolution crystal structure of Argos bound to Spitz, an EGFR ligand. Contrary to expectations and previous reports, Argos itself does not contain an EGF‐like domain. Instead, a trio of closely related domains (resembling a three‐finger toxin fold) 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 domain of Spitz. The three‐domain clamp of Argos resembles the human urokinase‐type plasminogen activator (uPA) receptor, which uses a similar mechanism to engulf the EGF‐like module of uPA. Our results indicate that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues.