Structure-function relationship of p53 tumour suppressor protein

多细胞生物体如人体的组织细胞以高度协调的方式发挥功能，以防止组织或器官内任何不期望的趋势的发展。环境压力和暴露于各种遗传毒性物质使我们的细胞处于突变的持续威胁之下，这些突变可以诱导癌症的发展。自然地，我们的细胞已经发展出多种防御机制来从健康组织中消除这些突变细胞，而这项任务是由许多称为肿瘤抑制因子的蛋白质启动和执行的。p53转录因子就是这样一种蛋白质，被称为“基因组的监护人”。p53参与我们染色体DNA的质量控制，其重要性因超过50%的人类癌症与p53基因突变有关而突出。由于对p53作用的深入的生物医学和生物化学研究，已经积累了大量的知识，但其参与和响应DNA损伤的潜在分子机制仍不清楚。要了解这个关键分子的结构-功能关系，需要捕捉分子在不同状态下以及与DNA复合时的一系列快照。p53反应元件内间隔区长度的天然多样性意味着研究p53-DNA相互作用将阐明转录因子和其他DNA结合蛋白的一般机制。p53分子内构象变化的可视化将揭示其功能机制，这将在实验中进一步探索。全长p53的第一个结构为我们进一步分析其与DNA的复合物和癌症相关的p53突变体提供了平台。在这个项目中，我们将使用伯克贝克学院最先进的电子显微镜设备在生理环境中分析p53分子。图像分析和对接已知的原子结构域将允许分析不同的构象的p53。

Tissue cells of multicellular organisms such as the human body function in a highly coordinated manner in order to prevent the development of any undesirable trends within a tissue or an organ. Environmental pressures and exposure to various genotoxic agents keeps our cells under the constant threat of mutations which can induce the development of cancer. Naturally our cells have developed multiple defense mechanisms to eliminate such mutated cells from healthy tissue and this task is initiated and performed by a number of proteins called tumour suppressors. p53 transcription factor is one such protein and has been termed the 'guardian of genome'. p53 is involved in quality control of our chromosomal DNAand its importance is highlighted by the fact that more than 50% of human cancers are associated with mutations in the p53 gene. A substantial wealth of knowledge has accumulated due to intensive biomedical and biochemical studies of p53's action but the underlying molecular mechanisms of its participation and response to DNA damage are still unclear. Understanding the structure-function relationship of this crucial molecule would require capturing a series of snapshots of the molecule in its different states and in complex with DNA. The natural diversity of the length of inner spacer in p53 response elements implies that study of p53-DNA interactions would elucidate the general mechanisms of transcription factors and other DNA-binding proteins. The visualisation of conformational changes within the p53 molecule will reveal the mechanism of its functioning that will be further explored experimentally. The first structure of the full length p53 gave us the launching platform for further analysis of its complexes with DNA and of cancer-relevant p53 mutants. In this project we will analyse the p53 molecules in a physiological environment using the state-of-art electron microscopy facilities in Birkbeck College. Image analysis and docking of known atomic structures of domains will allow analysis of different conformations of p53.