Garnier N, Genest D, Hebert E, Genest M
Centre de Biophysique Moléculaire CNRS, Orléans, France.
J Biomol Struct Dyn. 1994 Apr;11(5):983-1002. doi: 10.1080/07391102.1994.10508047.
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.
c-erbB2原癌基因编码一种185kDa的蛋白质（p185），该蛋白质在缬氨酸（Val）变为谷氨酸（Glu）的跨膜氨基酸取代后具有转化能力。这种转化能力似乎是由于蛋白质酪氨酸激酶胞质结构域的取代导致的组成型激活。这些观察结果促使我们评估野生型和转化型p185蛋白跨膜区域的结构和动力学行为，以了解该区域在转导机制中的作用。在真空中对对应于p185c-erbB2蛋白序列[651-679]及其转化突变体Val659→Glu659的两种肽进行了160皮秒的分子动力学模拟。这两个序列包括跨膜结构域，最初假定为α-螺旋构象。结果显示两种肽的柔韧性存在明显差异。在160皮秒的模拟过程中，非转化序列似乎相当灵活，在突变点[658-659]的连接处以及缬氨酸665-缬氨酸666位置检测到了几种构象变化。相反，对于采用稳定α-螺旋构象的突变序列未观察到转变。这种柔韧性的差异可以被假设为参与p185c-erbB2酪氨酸激酶活性调节的一个因素。
