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 significan tly reduced activity. HT1 is a chimeric protein that has the first seven re sidues of transforming growth factor-alpha and the sequence of heregulin-al pha from the first cysteine through the next 58 residues. The results demon strate that both proteins share the same fold, including the triple strande d beta-sheet formed by the N-terminus and the B-loop. Analysis of the chemi cal shifts indicates that there are perturbations to the side chain packing of the beta-sheet. The observed changes in the chemical shifts show an int eresting correspondence to the results from the homologue scan presented in the previous paper. These results indicate that the binding epitope for th e native receptor extends across the beta-sheet and includes residues Leu(1 79), Lys(181), Leu(209), and Lys(211). (C) 1998 Academic Press.