INFLUENCE OF A MUTATION IN THE TRANSMEMBRANE DOMAIN OF THE P185(C-ERBB2) ONCOGENE-ENCODED PROTEIN STUDIED BY MOLECULAR-DYNAMICS SIMULATIONS

The c-erbB2 proto-oncogene encodes for a protein of 185kDa(p185) which becomes transforming upon the Val-->Glu transmembrane amino acid subs titution. The transforming ability seems to be due to a substitution-r esulting constitutive activation of the tyrosine kinase cytosolic doma in of the protein. These observations prompted us to evaluate the stru ctural 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 simula tions in vacuo have been performed on two peptides corresponding to th e sequence [651-679] of p185(c-erbB2) protein and its transforming mut ant Val(659)-->Glu(659). These two sequences include the transmembrane domain and are initially postulated to be in an alpha-helix conformat ion. 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 p oint [658-659] and at position Val(665)-Val(666) during the 160 ps sim ulations. On the contrary, no transitions were observed for the mutate d sequence which adopts a stable alpha-helix conformation. This differ ence in flexibility could be hypothesized as a factor involved in the regulation of the tyrosine kinase activity of p185(c-erbB2).