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

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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.