Evidence for an alpha-helix -> pi-bulge helicity modulation for the neu/erbB-2 membrane-spanning segment. A H-1 NMR and circular dichroism study

The 35-residue peptide corresponding to the very hydrophobic transmembrane region of the tyrosine kinase receptor neu, Neu(TM35), has been synthesized . The peptide can be solubilized in millimolar concentrations in TFE or inc orporated into an SDS-water micellar solution or into well-hydrated DMPC/ D CPC bicelles. In all these media, circular dichroism demonstrated that the peptide adopts a helical structure for about 80% of its amino acids. The pe ptide is monomeric below 2 mM in TFE, as also determined by variable concen tration experiments. The three-dimensional solution structure in TFE has be en obtained by homonuclear proton NMR and shows a well-defined or-helix fro m residues 4 to 21, then pi -bulge from Ile(22) to Gly(28), and a final sho rt alpha -helix from positions 29 to 32. This experimental finding is in ag reement with structures predicted recently by molecular dynamics calculatio ns in a vacuum [Sajot, N., and Genest, M. (2000) Eur. Biophys. J. 28, 648-6 62]. The biological implications of a possible retention of this structure in a membrane environment are finally discussed.