Research project
Structures and Probes of Intrinsically Disordered Regions
- Start date: 4 January 2021
- End date: 3 January 2026
- Funder: Biotechnology and Biological Sciences Research Council (BBSRC)
- Partners and collaborators: University of Leeds, Astbury Centre for Structural Molecular Biology; University of Birmingham; University of Oxford, Department of Biochemistry; AstraZeneca; LifeArc
- Primary investigator: Professor Andrew Wilson, School of Chemistry
- Co-investigators: Prof. Richard Bayliss, Dr Takashi Ochi, Dr Tomlinson, Professor Sheena Radford
- Postgraduate students: Isha Mohan, Jack Roberts, Brian Shami-Inkindi, Emma Wood
Project title
Structures and Probes of Intrinsically Disordered Regions
Description
Proteins carry out the chemical reactions necessary for life and are used as building blocks to assemble key components of cells, which gives them their shape and structure.
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” change with time, how this influences their interactions with other proteins, how this impacts the life-cycle of healthy/unhealthy cells, and ultimately how to control these properties using chemistry to tackle a range of diseases.
Research overview
In this project, we will study a protein that plays an essential role in the cell’s life-cycle, Aurora-A.
What is Aurora-A?
Aurora-A is the master controller for cell division. When this process goes wrong, it can lead to cancer. However, cell division is also one of cancer's weaknesses and inhibiting Aurora-A is an effective way to stop cancer cells from proliferating.
Project objectives
In this project, we will 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.
Partners
University of Leeds, Astbury Centre for Structural Molecular Biology
University of Oxford, Department of Biochemistry
Impact
Key findings
In our most recent study, “CEP192 localises mitotic Aurora-A activity by priming its interaction with TPX2”, we have discovered more about how Aurora-A performs its role with other binding partners, CEP192 and TPX2.
We have revealed that:
- Aurora-A must first bind to CEP192 before it is passed to another binding partner TPX2 – this is important because it shows there’s a hierarchy of interactions.
- CEP192 competes against other Aurora-A binding partners by wrapping around it and obscuring their binding sites - explaining why it is first and has a greater role than expected.
This deeper knowledge about the process of bindings means we are one step further to designing molecules that block the individual steps in the process, a more precise approach than current inhibitors that completely disrupt Aurora-A activity.
Public engagement
May 2024
PhD researcher Jack Roberts presented at Pint of Science about the role of protein disorder in health and disease.
September 2023
Dr Jennifer Miles, Dr Matt Batchelor and Isha Mohan hosted two sixth form students on the In2Science scheme in the School of Molecular and Cellular Biology.
The students were introduced to numerous techniques that are used daily on the SPIDR project and given hands on experience in protein crystallisation.
Dr Miles also presented her research to members of the general public in York as part of Soapbox Science. Dr Miles’ aim was to present some of the techniques we use on the SPIDR project and why we do them, and to promote structural biology and women in STEM.
Soapbox Science is a novel public outreach platform for promoting women and non-binary scientists and their science.
May 2022
Professor Andy Wilson visited Notre Dame 6th form College in Leeds to give a talk to their lower sixth students about his career.
During his visit, Andy outlined the drug discovery process and explained the important role that chemists play in this process. He also highlighted the particular challenges associated with discovering new medicines for targets such as protein-protein interactions (PPIs), which typically involve intrinsically disordered domains.
The SPIDR team also attended Be Curious 2022 – the University of Leeds’ flagship public engagement event.
At the event, the team hosted a ‘Lucky IDP’ stand which illustrated how proteins are made of long strings of amino acids. Academics explained how ordered Proteins fold into 3-dimensional shapes to do their jobs inside cells whilst Intrinsically Disordered Proteins (IDPs) use their floppy unfolded strings like “molecular velcro” to recruit partner proteins to do jobs. Visitors could also “fish” in our cell pond with their Lucky IDP to catch a partner protein.