Conformation of the transmembrane domain of the epidermal growth factor receptor.
The transmembrane domain of growth factor receptors, such as the epidermal growth factor receptor (EGFR) and the related c-erbB-2/neu oncogene protein, has been implicated in the process of receptor dimerization and mitogenic signal transduction, and hence in cellular transformation and oncogenesis. Amino acid substitutions in the transmembrane domain of the c-erbB-2/neu protein that cause a transforming effect may exert this effect through a conformational change from a bend conformation to an alpha-helical structure in this region of the protein, but similar amino acid substitutions at homologous positions in the transmembrane 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 structural effects, we have used conformational energy analysis to determine the preferred three-dimensional structures for the nonapeptide sequence of the transmembrane domain of the EGFR from residues 623-631 with Val or Glu at position 627. The global minimum energy conformations of both nonapeptides were found to be non-alpha-helical with bends at positions 624-625 and 627-628. The failure of the Val-->Glu substitution to produce a conformational change to an alpha-helix in this region may be responsible for its lack of transforming effect. However, the presence of higher energy alpha-helical conformations for the nonapeptide from the normal EGFR may provide an explanation for the presence of a transforming effect from overexpression of the EGFR.
Brandt-Rauf
P W
PW
Division of Environmental Sciences, Columbia University, New York, New York 10032.
Monaco
R
R
Pincus
M R
MR
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D066246:ErbB Receptors / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases
D066246:ErbB Receptors; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases