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Conformation of the transmembrane domain of the epidermal growth factor receptor
P W Brandt-Rauf1, R Monaco, M R Pincus
1Division of Environmental Sciences, Columbia University, New York, New York 10032.
Abstract:
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.
Insights
Substitutions in the transmembrane domain of epidermal growth factor receptor (EGFR) may not cause transformation due to a lack of alpha-helical structure. However, EGFR overexpression might lead to transformation via higher energy alpha-helical conformations.
Area of Science:
- Molecular Biology
- Biophysics
- Oncogenesis
Background:
- The transmembrane domain of growth factor receptors, including EGFR and c-erbB-2/neu, is crucial for signal transduction and oncogenesis.
- Amino acid substitutions in the c-erbB-2/neu transmembrane domain can induce transformation, potentially via conformational changes to an alpha-helical structure.
Purpose of the Study:
- To investigate the structural basis for the lack of transforming effect of specific amino acid substitutions in the EGFR transmembrane domain.
- To determine the preferred three-dimensional structures of EGFR transmembrane domain nonapeptides with different amino acid substitutions.
Main Methods:
- Conformational energy analysis was employed.
- The study focused on the nonapeptide sequence (residues 623-631) of the EGFR transmembrane domain.
- Both Val and Glu at position 627 were analyzed.
Main Results:
- The global minimum energy conformations for both Val and Glu nonapeptides were non-alpha-helical, featuring bends.
- The Val to Glu substitution at position 627 in EGFR did not induce an alpha-helical structure.
- Higher energy alpha-helical conformations were identified for the normal EGFR nonapeptide.
Conclusions:
- The failure of the Val-->Glu substitution to induce an alpha-helical structure may explain its lack of transforming effect in EGFR.
- The existence of higher energy alpha-helical conformations in the normal EGFR transmembrane domain might contribute to transformation upon overexpression.