HOMOLOG SCANNING MUTAGENESIS OF HEREGULIN REVEALS RECEPTOR-SPECIFIC BINDING EPITOPES

The EGF domain of heregulin has all the receptor binding characteristi cs of full-length heregulin and has strong homology to the ligands for erbB-1. Despite this, it does not bind erbB-1 but instead binds erbB- 3 and erbB-4, The sequence similarity between HRG and the erbB-1 ligan ds suggest that a few residues are responsible for receptor binding sp ecificity. To determine the sequences involved in receptor binding, we performed homologue scanning mutagenesis on the EGF domain of HRG alp ha using sequences of TGF alpha or EGF. We found three sets of mutatio ns in the N-terminal subdomain that were responsible for receptor bind ing specificity, Mutations in the C-terminal subdomain affected the bi nding affinity, but did appear to confer any specificity. (C) 1998 Aad emic Press.