Correlation of the structure of the transmembrane domain of the neu oncogene-encoded p185 protein with its function.
Correlation of the structure of the transmembrane domain of the neu oncogene-encoded p185 protein with its function.
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neu癌基因编码的p185蛋白跨膜结构域的结构与其功能的相关性。
DOI：
10.1073/pnas.87.21.8660
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发表时间：
1990
影响因子：
11.1
通讯作者：
Pincus,MR
中科院分区：
文献类型：
--
作者：
Brandt-Rauf,PW;Rackovsky,S;Pincus,MR
neu癌基因的人类同源物经常在人类肿瘤中发现。已知neu癌基因编码的p185蛋白产物的跨膜结构域中664位的某些氨基酸取代会引起细胞的恶性转化。基于ECEPP的构象能分析（多肽的经验构象能程序），我们先前已经确定了p185蛋白跨膜结构域的优选三维结构，（谷氨酸）和非转化（缬氨酸）取代的关键位置664，并发现，全球最小-在非转化蛋白质中该区域的能量构象包含一个尖锐的弯曲，而转化蛋白质中该区域的整体最小能量构象完全是α-螺旋。我们现在证明，这一结果适用于其他已知的非转化（甘氨酸，组氨酸，酪氨酸和赖氨酸）和转化（谷氨酰胺）取代位置664。此外，对结果的简单统计热力学分析表明，约85%的每个非转化序列在位置664和665处存在弯曲，而约90%的每个转化序列作为α-螺旋存在。约9%的非转化序列以α-螺旋形式存在。这些结果表明，如果正常蛋白质的细胞内浓度增加至少10倍，从而通过该因子增加α-螺旋形式，则应导致细胞转化。这一结论得到了遗传实验的直接支持，在这些实验中，正常蛋白质的这种过表达水平是伴随着细胞转化而实现的。
The human homologue of the neu oncogene is frequently found in human tumors. Certain amino acid substitutions at position 664 in the transmembrane domain of the neu oncogene-encoded p185 protein product are known to cause malignant transformation of cells. Using conformational energy analysis based on ECEPP (empirical conformational energies for polypeptides program), we have previously determined the preferred three-dimensional structures for the transmembrane domain of the p185 protein with a transforming (glutamic acid) and a nontransforming (valine) substitution at the critical position 664 and found that the global minimum-energy conformation of this region in the nontransforming protein contains a sharp bend, whereas the global minimum-energy conformation for this region from the transforming protein is entirely alpha-helical. We now demonstrate that this result holds for other known nontransforming (glycine, histidine, tyrosine, and lysine) and transforming (glutamine) substitutions at position 664. Furthermore, a simple statistical thermodynamic analysis of the results indicates that approximately 85% of each of the nontransforming sequences exist with the bend at positions 664 and 665, while approximately 90% of each of the transforming sequences exist as an alpha-helix. About 9% of the nontransforming sequences exist as the alpha-helix. These results suggest that if the intracellular concentration of the normal protein is increased at least 10-fold, thereby increasing the alpha-helical form by this factor, cell transformation should result. This conclusion is directly supported by genetic experiments in which this level of overexpression of the normal protein was achieved with attendant cell transformation.