Molecular dynamics of the full-length p53 monomer
Molecular dynamics of the full-length p53 monomer
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DOI：
10.4161/cc.26162
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发表时间：
2013-09-15
期刊：
影响因子：
4.3
通讯作者：
Melino, Gerry
中科院分区：
文献类型：
--
作者：
Chillemi, Giovanni;Davidovich, Pavel;Melino, Gerry
p53蛋白在很大比例的人类肿瘤中经常发生突变，其中它似乎获得了促进肿瘤发生和进展的功能获得性活性。一种可能的机制是突变型p53蛋白与其他蛋白质（包括同一家族的成员，即p63和p73）物理相互作用的能力，使它们的功能失活。假设这种相互作用可能发生在单体的水平上，为了研究这种相互作用的分子基础，在这里，我们对野生型p53单体蛋白的结构灵活性进行了采样。结果表明，在DNA结合结构域中具有高达850 ns的强稳定性，在N-末端反式激活结构域（TAD 1和TAD 2）以及C-末端区域（四聚化结构域）中具有较大的灵活性。在N端或C端与DNA结合结构域之间以及N端与C端之间检测到几个稳定的氢键。基本动力学分析突出了强烈相关的运动，涉及TAD 1和脯氨酸丰富的区域在N-末端结构域，在C-末端结构域的四聚化区域;在DNA结合区域的Lys 120。本文提出的模型是进一步研究整个蛋白质四聚体及其突变体的起点。
The p53 protein is frequently mutated in a very large proportion of human tumors, where it seems to acquire gain-of-function activity that facilitates tumor onset and progression. A possible mechanism is the ability of mutant p53 proteins to physically interact with other proteins, including members of the same family, namely p63 and p73, inactivating their function. Assuming that this interaction might occurs at the level of the monomer, to investigate the molecular basis for this interaction, here, we sample the structural flexibility of the wild-type p53 monomeric protein. The results show a strong stability up to 850 ns in the DNA binding domain, with major flexibility in the N-terminal transactivations domains (TAD1 and TAD2) as well as in the C-terminal region (tetramerization domain). Several stable hydrogen bonds have been detected between N-terminal or C-terminal and DNA binding domain, and also between N-terminal and C-terminal. Essential dynamics analysis highlights strongly correlated movements involving TAD1 and the proline-rich region in the N-terminal domain, the tetramerization region in the C-terminal domain; Lys120 in the DNA binding region. The herein presented model is a starting point for further investigation of the whole protein tetramer as well as of its mutants.