EGFR ligand sequestration by Argos
Mark Lemmon group (University of Pennsylvania)
Mark Lemmon's group of the University of Pennsylvania
published a major paper aimed at defeating cancer. Members of the epidermal
growth factor receptor (EGFR) family and their activating ligands are
essential regulators of diverse developmental processes, and inappropriate
activation of these receptors is a key feature of many human cancers. A
natural secreted antagonist of EGFR signalling, called Argos, was identified
in Drosophila, and the investigators previously showed that Argos functions
by directly binding and sequestering growth factor ligands that activate
EGFR. Using data collected at GM/CA-CAT and at the ALS, the investigators
determined the crystal structure of Argos bound to an EGFR ligand, Spitz.
Contrary to expectations, Argos contains no EGF-like domain. Instead, three
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. The individual Argos domains share unexpected
structural similarities with two families of other receptors. The structures
presented here define requirements for the design of artificial
EGF-sequestering proteins that would be valuable anti-cancer therapeutics.
Figure: Argos' sequestration of Spitz.
Klein, DE, Stayrook, SE, Shi, F, Narayan, K, Lemmon, MA. Structural basis
for EGFR ligand sequestration by Argos, Nature 453, 1271-1275 (2008). DOI: