Deciphering the function of intrinsically disordered protein regions in a cellular context

蛋白质进行生命所必需的化学反应，并被用作组装细胞关键成分的积木，赋予它们形状和结构完整性。在细胞的生命周期中，根据需要产生不同的蛋白质，然后当它们完成工作时回收利用。为了完成它们的工作，蛋白质本身可能会经历化学修饰，与其他蛋白质相互作用，并采用各种不同的形状。我们对蛋白质形态、结构和功能的了解，对于进一步加深我们对生命的分子理解是非常有用的，从而导致成功的药物发现努力，改进作物生产的方法，以及其他具有经济和社会效益的应用。虽然大多数蛋白质采用规则的3D形状，但现在公认的是，许多蛋白质的大段被称为固有无序区(IDR)，没有固定的形状。这些“变形”特性允许含有它们的蛋白质在不同的时间和细胞的不同部分执行不同的工作，通过动态地采用不同的形状来响应他们所处的环境。因此，为了真正理解“生命的分子规则”，有必要了解这些“变形因子”的结构如何随时间变化，这如何影响它们与其他蛋白质的相互作用，如何影响健康/不健康的细胞生命周期，以及最终如何使用化学手段控制这些特性。在这项研究中，我们将研究一种在细胞生命周期(Aurora-A)中发挥关键作用的蛋白质，例如在细胞分裂中，这一过程在癌症中变得有缺陷，使其成为抗癌药物发现努力的焦点，但尚未成功。Aurora-A通过与多种不同的“变形”蛋白质相互作用，在不同的时间和细胞的不同部位完成不同的工作。我们将使用一种集成的最先进的化学和生物学方法来表征变形蛋白质和Aurora-A之间何时、何地以及哪些相互作用定义了它的生物学功能。通过这样做，我们将找到关闭Aurora-A和特定变形因子之间相互作用的方法，这可以用来进一步了解这些蛋白质的功能作用，并为药物发现提供起点。大约三分之一的人类蛋白质被认为具有内在的无序区域，我们的研究将帮助生物学家调查这些鲜为人知的蛋白质的性质和作用。从长远来看，操控“变形”蛋白质的能力将为开发治疗多种疾病的药物开辟一条新的途径。

Proteins carry out the chemical reactions necessary for life, and are used as building blocks to assemble key components of cells, giving them shape and structural integrity. During a cell's life cycle, different proteins are produced as needed and then recycled when they have finished their work. To perform their jobs, proteins may themselves undergo chemical modifications, interact with other proteins and adopt a variety of different shapes. Our understanding of protein shape, structure and function has been enormously useful in furthering our molecular understanding of life, leading to successful drug-discovery efforts, methods to improve crop production and other applications with economic and societal benefits. While most proteins adopt a regular 3D shape, it is now accepted that large sections of many proteins termed intrinsically disordered regions (IDRs) have no fixed shape. These "shape-shifting" properties allow the proteins that contain them to perform different jobs at different times and in different parts of the cell by dynamically adopting different shapes in response to their environment. To truly understand the "molecular rules of life", it is therefore necessary to understand how the structures of these "shape-shifters" changes with time, how this influences what other proteins they interact with, how this impacts on the healthy/unhealthy cells life-cycle and ultimately how to control these properties using chemistry. In this research we will study a protein that plays an essential role in the cells life-cycle (Aurora-A) e.g. in cell-division, a process that becomes defective in cancer making it a focus of anticancer drug discovery efforts that have not yet been successful. Aurora-A fulfils different jobs at different times and in different parts of the cell by interacting with multiple different "shape-shifting" proteins. We will use an integrated and state-of-the-art chemical and biological approach to characterise when, where and which interactions between shape-shifting proteins and Aurora-A define its biological function. In doing so, we will identify methods to switch off the interactions between Aurora-A and specific shape-shifters, which can be used to further understand the functional role of these proteins and provide starting points for drug discovery. About a third of human proteins are thought to have an intrinsically disordered region, and our study will help biologists to investigate the properties and roles of these poorly-understood proteins. In the longer term, the ability to manipulate "shape-shifting" proteins will open up a new route to developing medicines to treat a wide range of diseases.