Probing life-and-death switches using "designer" p53

使用“设计者”探测生死开关 p53

• 批准号: BB/W015730/1
• 负责人: Manuel Muller
• 金额: $ 58.45万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW015730%2F1
• 关键词: Probing; life; death; switches; using

Proteins are molecular machines that control most biological processes. Among them, a protein called p53 acts as a safeguard against cancer in that it instructs cancers cells to self-destruct before they can multiply. Accordingly, malfunction of p53 is a prerequisite for most human cancers. It is therefore important to understand the molecular mechanism by which p53 operates, alone and in conjunction with other protein partners. At the molecular level, p53 receives a multitude of stress signals from cells that are deposited onto p53 in the form of covalent biochemical signals, so-called post-translational modifications. These signals form a type of code which p53 then integrates into a defined cellular response ranging from "business as usual" and targeted repair processes all the way to the initiation of cell death protocols. However, how exactly p53 and its protein partners decode post-translational modifications remains enigmatic. This proposal aims to unravel how p53 makes such life-and-death decisions by determining how specific post-translational modifications change the functional interactions between p53 and its protein partners. We are able to achieve this goal because we have developed chemical tools that allows us to synthesise "designer p53" carrying defined modifications. Upon synthesising new versions of "designer p53", we aim to reconstitute biochemical signalling processes in the test tube, allowing us to measure the effect of post-translational modifications under controlled circumstances. Specifically, we aim to address how p53 modifications act as molecular docking platforms to connect with known and new protein partners and convert these interactions into further biochemical signals. In this way, we will illuminate how p53 acts as a molecular signal integration device which sets the foundation for new quantitative insights into its action as a tumour suppressor.

蛋白质是控制大多数生物过程的分子机器。其中，一种名为p53的蛋白质是预防癌症的保障，因为它指示癌细胞在繁殖之前自毁。因此，p53的功能障碍是大多数人类癌症的先决条件。因此，重要的是要了解p53单独和与其他蛋白质合作伙伴一起运作的分子机制。在分子水平上，p53从细胞接收大量的应激信号，这些信号以共价生化信号的形式沉积在p53上，即所谓的翻译后修饰。这些信号形成一种类型的代码，然后p53将其整合到定义的细胞反应中，从“照常营业”和靶向修复过程一直到启动细胞死亡方案。然而，p53和它的蛋白质伴侣究竟如何解码翻译后修饰仍然是个谜。该提案旨在通过确定特定的翻译后修饰如何改变p53与其蛋白质伴侣之间的功能相互作用来揭示p53如何做出这种生死决定。我们能够实现这一目标，因为我们已经开发出化学工具，使我们能够合成“设计师p53”携带定义的修改。在合成新版本的“设计者p53”后，我们的目标是在试管中重建生化信号传导过程，使我们能够在受控的情况下测量翻译后修饰的效果。具体来说，我们的目标是解决p53修饰如何作为分子对接平台与已知和新的蛋白质伴侣连接，并将这些相互作用转化为进一步的生化信号。通过这种方式，我们将阐明p53如何作为一种分子信号整合装置，为新的定量了解其作为肿瘤抑制因子的作用奠定基础。