title: Influence of a mutation in the transmembrane domain of the p185c-erbB2 oncogene-encoded protein studied by molecular dynamics simulations.
abstract: The c-erbB2 proto-oncogene encodes for a protein of 185kDa (p185) which becomes transforming upon the Val-->Glu transmembrane amino acid substitution. The transforming ability seems to be due to a substitution-resulting constitutive activation of the tyrosine kinase cytosolic domain of the protein. These observations prompted us to evaluate the structural and dynamical behavior of the transmembrane region of the wild and transforming p185 protein in order to understand the role of this region in the transduction mechanism. 160 ps molecular dynamics simulations in vacuo have been performed on two peptides corresponding to the sequence [651-679] of p185c-erbB2 protein and its transforming mutant Val659-->Glu659. These two sequences include the transmembrane domain and are initially postulated to be in an alpha-helix conformation. Noticeable differences in the flexibility of the two peptides are shown. The nontransforming sequence seems rather flexible and several conformational changes are detected at the junction of the mutation point [658-659] and at position Val665-Val666 during the 160 ps simulations. On the contrary, no transitions were observed for the mutated sequence which adopts a stable alpha-helix conformation. This difference in flexibility could be hypothesized as a factor involved in the regulation of the tyrosine kinase activity of p185c-erbB2.
authors.affiliation: Centre de Biophysique Moléculaire CNRS, Orléans, France.
authors.forename: N
authors.initials: N
authors.lastname: Garnier
authors.forename: D
authors.initials: D
authors.lastname: Genest
authors.forename: E
authors.initials: E
authors.lastname: Hebert
authors.forename: M
authors.initials: M
authors.lastname: Genest
mesh_terms: D000595:Amino Acid Sequence; D005973:Glutamine / Q000737:chemistry; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D011519:Proto-Oncogenes; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014633:Valine / Q000737:chemistry
chemical_list: D005973:Glutamine; D018719:Erb-b2 Receptor Tyrosine Kinases; D014633:Valine