Conformational changes induced by the transforming amino acid substitution in the transmembrane domain of the neu oncogene-encoded p185 protein.
The neu oncogene is frequently found in certain types of human carcinomas and has been shown to be activated in animal models by nitrosourea-induced mutation. The activating mutation in the neu oncogene results in the substitution of a glutamic acid for a valine at position 664 in the transmembrane domain of the encoded protein product of 185 kda (designated p185), which, on the basis of homology studies, is presumed to be a receptor for an as yet unidentified growth factor. It has been proposed that activating amino acid substitutions in this region of p185 lead to a conformational change in the protein which causes signal transduction via an increase in tyrosine kinase activity in the absence of any external signal. Using conformational energy analysis, we have determined the preferred three-dimensional structures for the transmembrane decapeptide (residues 658-667) of the p185 protein with valine and glutamic acid at the critical position 664. The results indicate that the global minimum energy conformation of the decapeptide from the normal protein with Val at position 664 is an alpha-helix with a sharp bend (CD conformation at residues 664 and 665) in this region, whereas the global minimum conformation for the decapeptide from the mutant transforming protein with Glu at position 664 assumes an all alpha-helical configuration. Furthermore, the second highest energy conformation for the decapeptide from the normal protein is identical to the global minimum energy conformation for the decapeptide from the transforming protein, providing a possible explanation why overexpression of the normal protein also has a transforming effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Brandt-Rauf
P W
PW
Department of Medicine, Columbia-Presbyterian Medical Center, New York, New York 10032.
Pincus
M R
MR
Chen
J M
JM
D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000032:analysis; D002471:Cell Transformation, Neoplastic; D005971:Glutamates; D018698:Glutamic Acid; D008969:Molecular Sequence Data; D009842:Oligopeptides; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014633:Valine
D005971:Glutamates; D018698:Glutamic Acid; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014633:Valine