CONFORMATION OF THE TRANSMEMBRANE DOMAIN OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR

The transmembrane domain of growth factor receptors, such as the epide rmal growth factor receptor (EGFR) and the related c-erbB-2/neu oncoge ne protein, has been implicated in the process of receptor dimerizatio n and mitogenic signal transduction, and hence in cellular transformat ion and oncogenesis. Amino acid substitutions in the transmembrane dom ain of the c-erbB-2/neu protein that cause a transforming effect may e xert this effect through a conformational change from a bend conformat ion to an a-helical structure in this region of the protein, but simil ar amino acid substitutions at homologous positions in the transmembra ne domain of the EGFR (e.g., Val-->Glu at position 627) fail to have a transforming effect. To examine whether this failure may be due to st ructural effects, we have used conformational energy analysis to deter mine the preferred three-dimensional structures for the nonapeptide se quence of the transmembrane domain of the EGFR from residues 623-631 w ith Val or Glu at position 627. The global minimum energy conformation s of both nonapeptides were found to be non-a-helical with bends at po sitions 624-625 and 627-628. The failure of the Val-->Glu substitution to produce a conformational change to an a-helix in this region may b e responsible for its lack of transforming effect. However, the presen ce of higher energy alpha-helical conformations for the nonapeptide fr om the normal EGFR may provide an explanation for the presence of a tr ansforming effect from overexpression of the EGFR.