Brandt-Rauf P W, Monaco R, Pincus M R
Department of Medicine and Comprehensive Cancer Center, Columbia University, New York, NY 10032.
Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9262-6. doi: 10.1073/pnas.91.20.9262.
The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. A considerable number of environmentally induced, cancer-related p53 mutations in human tumors have been found in a highly conserved proline-rich sequence of the p53 protein encompassed by amino acid residues 147-158. Using conformational energy analysis based on ECEPP (Empirical Conformational Energy for Peptides Program), we have determined the low-energy three-dimensional structures for this dodecapeptide sequence for the human wild-type p53 protein and three environmentally induced, cancer-related mutant p53 proteins with His-151, Ser-152, and Val-154, respectively. The results suggest that the wild-type sequence adopts a well-defined low-energy conformation and that the mutant peptides adopt well-defined conformations that are distinctly different from the conformation of the wild-type peptide. These results are consistent with experimental conformational studies demonstrating altered detectability of antigenic epitopes in wild-type and mutant p53 proteins. These results suggest that the oncogenic effects of these environmentally induced, cancer-related, mutant p53 proteins may be mediated by distinct local conformational changes in the protein.
肿瘤抑制基因p53已被确定为人类癌症中最常见的基因改变靶点。在人类肿瘤中，大量与癌症相关的、由环境诱导的p53突变，出现在p53蛋白富含脯氨酸的高度保守序列中，该序列由氨基酸残基147 - 158组成。利用基于ECEPP（肽的经验构象能量程序）的构象能量分析，我们确定了人类野生型p53蛋白的这个十二肽序列以及三种分别带有His-151、Ser-152和Val-154的、由环境诱导的、与癌症相关的突变p53蛋白的低能量三维结构。结果表明，野生型序列呈现出明确的低能量构象，而突变肽则呈现出与野生型肽构象明显不同的明确构象。这些结果与实验性构象研究一致，该研究表明野生型和突变型p53蛋白中抗原表位的可检测性发生了改变。这些结果表明，这些由环境诱导的、与癌症相关的突变p53蛋白的致癌作用，可能是由蛋白质中不同的局部构象变化介导的。
