- Start date: 1 January 2021
- End date: 1 January 2026
- Value: £5,400,000
- Partners and collaborators: University of Oxford, AstraZeneca, LifeArc
- Primary investigator: 00917043
- Co-investigators: Dr Megan Wright
- Co-investigators (additional Faculties): Professor Sheena Radford, Professor Richard Bayliss, Dr. Darren Tomlinson, Professor Colin A. Johnson
- External co-investigators: Dr Fanni Gergely (University of Oxford)
SPIDR is a £5.4M five-year collaborative strategic Longer and Larger programme grant (sLoLa), funded by the Biotechnology and Biological Sciences Research Council, between the following organizations: University of Leeds University of Oxford AstraZeneca LifeArc 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.
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 many 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.
To truly understand the “molecular rules of life”, it is necessary to understand how the structures of these “shape-shifters” changes with time, how this influences their interactions with other proteins, how this impacts on the life-cycle of healthy/unhealthy cells, and ultimately how to control these properties using chemistry.
In this sLoLa, we will study a protein that plays an essential role in the cell’s 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.
The overall aim is to develop and use a state-of-the-art, integrated chemical and biological toolkit to understand and manipulate interactions of IDRs with Aurora-A in vitro and in cells.
Intrinsically disordered regions (IDRs), are ubiquitous stretches of protein that do not adopt a stable structure, are a major class of protein structure found in all living organisms and viruses, and, are predicted to be present in around a third of eukaryotic proteins. IDRs can, in a regulated manner:
(i) undergo disorder-order transition to adopt a functional, structured conformation e.g. through protein-protein interactions (PPIs) involving one or two IDR partners
(ii) contribute to phase separation promoting assembly of membraneless organelles and signalling complexes
(iii) regulate the function of adjacent ordered domains of the protein in which they lie.
The timeframe upon which dynamic conformational transitions occurs can affect a protein’s interactome and therefore crucially, its function. IDRs and their order-disorder transitions regulate diverse functional proteins (and thus cellular processes) incl.: transcription factor (TF) complexes, chaperones, DNA damage repair complexes, cytoskeleton scaffolding, and import/export complexes. IDRs are important and overrepresented in key signalling and disease pathways.
For all these classes of protein, the ability to understand and target IDR-dependent PPI interactomes with selective and spatiotemporal resolution would provide a major step forward in our understanding of biological mechanisms and, in the longer-term, our ability to develop targeted interventions.
This programme of research focuses on a specific system of IDRs that regulate a range of vital cellular functions through a common factor, the protein kinase Aurora-A. Each IDR in this system achieves a distinct function by localizing Aurora-A to a different subcellular compartment, regulating its catalytic activity, and forming a multivalent complex that brings additional components of the relevant pathway into kinase proximity.
Our goals are to ascertain how different IDR partners bind Aurora-A’s surface, how the structure and dynamics of IDRs alter upon Aurora-A interaction, and how the properties of the IDRs and their interactions relate to the dynamics of Aurora-A localisation and activation in cells.
Contextualizing molecular mechanisms within the framework of Aurora-A’s interactome to understand functional outcome, will allow us to: Assign IDR-dependent PPIs of Aurora-A to a functional outcome, leading to new methods for mechanistically precise interventions to disrupt them. Design and generate IDR-specific chemical and biological tools to dissect complex cellular mechanisms. Deliver broader understanding of how the dynamics of IDRs direct and scaffold PPIs in distinct locations to achieve spatially and temporally specific activities.