The solution structure of heregulin-alpha and a N-terminal mutant with suppressed activity

NMR spectroscopy is used to compare the structure of the EGF-like domain of heregulin-alpha and HT1, a mutated form of heregulin-alpha with significantly reduced activity. HT1 is a chimeric protein that has the first seven residues of transforming growth factor-alpha and the sequence of heregulin-alpha from the first cysteine through the next 58 residues. The results demonstrate that both proteins share the same fold, including the triple stranded beta-sheet formed by the N-terminus and the B-loop. Analysis of the chemical shifts indicates that there are perturbations to the side chain packing of the beta-sheet. The observed changes in the chemical shifts show an interesting correspondence to the results from the homologue scan presented in the previous paper. These results indicate that the binding epitope for the native receptor extends across the beta-sheet and includes residues Leu179, Lys181, Leu209, and Lys211.