THE STRUCTURAL BASIS FOR THE SPECIFICITY OF EPIDERMAL GROWTH-FACTOR AND HEREGULIN BINDING

Heregulin is a ligand for the erbB3 and erbB4 receptors, with a region of high homology to epidermal growth factor (EGF). Despite this homol ogy, these ligands bind to their corresponding receptors with great sp ecificity. We report here the synthesis of heregulin beta 177-241 and show that a region consisting of amino acids 177-226 is sufficient bot h for binding and stimulation of receptor phosphorylation. Studies of chimeric EGF/heregulin peptides revealed that amino acids 177-181 of h eregulin provide the specificity for binding to the heregulin receptor . The substitution of amino acids 177-181 of heregulin for the N termi nus of EGF produced a unique bifunctional agonist that binds with high affinity to both the EGF receptor and the heregulin receptor.