Abstract
The transmembrane domain of growth factor receptors, such as the epidermal growth factor receptor (EGFR) and the relatedc-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 thec-erbB-2/neu protein that cause a transforming effect may exert this effect through a conformational change from a bend conformation to anα-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-α-helical with bends at positions 624–625 and 627–628. The failure of the Val→Glu substitution to produce a conformational change to anα-helix in this region may be responsible for its lack of transforming effect. However, the presence of higher energyα-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.
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References
Bargmann, C. I., Hung, M.-C., and Weinberg, R. A. (1986).Nature 319, 226–230.
Bargmann, C. I., and Weinberg, R. A. (1988).EMBO J. 7, 2043–2052.
Brandt-Rauf, P. W., DeVivo, I., Dykes, D. C., and Pincus, M. R. (1992).J. Biomol. Struct. Dyn. 10, 253–264.
Brandt-Rauf, P. W., Pincus, M. R., and Carney, W. P. (1994).Crit. Rev. Oncogenesis in press.
Brandt-Rauf, P. W., Pincus, M. R., and Chen, J. (1989).J. Protein Chem. 8, 749–756.
Brandt-Rauf, P. W., Rackovsky, S., and Pincus, M. R. (1990).Proc. Natl. Acad. Sci. USA 87, 8660–8664.
Cao, H., Banglaore, L., Bormann, B. J., and Stern, D. F. (1992).EMBO J. 11, 923–932.
Carpenter, C. D., Ingraham, H. A., Cochet, C., Walton, G. M., Lazar, C. S., Sowadski, J. M., Rosenfeld, M. G., and Gill, G. N. (1991).J. Biol. Chem. 266, 5750–5755.
Coussens, L., Yang-Feng, T. L., Liao, Y.-C., Chen, E., Grey, A., McGrath, J., Seeburg, P. H., Lieberman, T. A., Schlessinger, J., Francke, U., Levinson, A., and Ullrich, A. (1985).Science 230, 1132–1139.
Di Fiore, P. P., Pierce, J. H., Fleming, T. P., Hazan, R., Ullrich, A., King, C. R., Schlessinger, J., and Aaronson, S. A. (1987).Cell 51, 1063–1070.
Gullick, W. J. (1988). InHormones and their Actions, Part II (Cooke, B. A., King, R. J. B., and van der Molen, H. J., eds), Elsevier, Amsterdam, pp. 349–360.
Gullick, W. J. (1991).Br. Med. Bull. 47, 87–98.
Nemethy, G., Pottle, M. S., and Scheraga, H. A. (1983).J. Phys. Chem. 87, 1883–1887.
Nemethy, G., Gibson, K. D., Palmer, K. A., Yoon, C. N., Paterlini, G., Zagari, A., Rumsey, S., and Scheraga, H. A. (1992).J. Phys. Chem. 96, 6472–6484.
Pincus, M. R. (1988).Int. J. Quantum Chem. Quantum Biol. Symp. 15, 209–220.
Pincus, M. R. (1992).Biopolymers 32, 347–351.
Pincus, M. R., Chung, D., Dykes, D. C., Brandt-Rauf, P. W., Weinstein, I. B., Yamaizumi, Z., and Nishimura, S. (1992).Ann. Clin. Lab. Science 22, 323–342.
Ponnuswamy, P. K., Warme, P. K., and Scheraga, H. A. (1973).Proc. Natl. Acad. Sci. USA 70, 830–833.
Scheraga, H. A. (1989).Chem. Scripta 29A, 3–13.
Segatto, O., King, C. R., Pierce, J. H., Di Fiore, P. P., and Aaronson, S. A. (1988)Mol. Cell. Biol. 8, 5570–5574.
Shah, D., Chen, J. M., Carty, R. P., Pincus, M. R., and Scheraga, H. A. (1989).Int. J. Peptide Protein Res. 34, 325–332.
Sternberg, M. J. E., and Gullick, W. J. (1990).Protein Engng. 3, 245–248.
Ullrich, A., Coussens, L., Hayflick, J. S., Dull, T. J., Grey, A., Tam, A. W., Lee, J., Yarden, Y., Libermann, T. A., Schlessinger, J., Downword, J., Mayes, E. L. V., Whittle, N., Waterfield, M. D., and Seeburg, P. H. (1981).Nature 309, 418–425.
Ullrich, A., and Schlessinger, J. (1990).Cell 61, 203–212.
Vasquez, M., Nemethy, G., and Scheraga, H. A. (1983).Macromolecules 16, 1043–1049.
Yarden, Y., and Ullrich, A. (1988).Ann. Rev. Biochem. 57, 443–478.
Zimmerman, S. S., Pottle, M. S., Nemethy, G., and Scheraga, H. A. (1977).Macromolecules 10, 1–9.
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Brandt-Kauf, P.W., Monaco, R. & Pincus, M.R. Conformation of the transmembrane domain of the epidermal growth factor receptor. J Protein Chem 13, 227–231 (1994). https://doi.org/10.1007/BF01891980
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DOI: https://doi.org/10.1007/BF01891980