Investigating the role of mutant Triple T chaperone in ATM assembly in Ataxia Telangiectasia
Research Project information
Principal researcher: Dr Mohinder Pal
Institute: University of Kent, UK
Cost: £249,806 over 36 months partnership with the A-T Society (UK), AEFAT (Spain) and BrAshA-T (Australia)
Start Date: TBC – currently recruiting
What are the researchers proposing to do?
A-T is caused by the loss of a protein called the ATM protein that participates in the repair of damage to DNA. Most mutations in the ATM gene cause the encoded protein to become unstable, resulting in a complete absence of ATM in cells in most A-T patients. Why this occurs is unknown. ATM requires helper proteins called molecular chaperones or chaperone complexes to assemble it correctly into a fully functional protein. Recent research shows that inherited mutations in these chaperone proteins can make the ATM protein unstable, and patients develop clinical symptoms that overlap with A-T disease. Despite this, it needs to be clarified how these chaperone proteins function to stabilise ATM and how patient-associated mutations in these chaperones affect this process.
The team in Kent seek to define precisely how these chaperone proteins interact with ATM. Electron microscopy will produce detailed images of the atomic structure of ATM bound to the chaperone complex. From these images, it should be possible to understand how mutations in these chaperones impact the assembly of the ATM protein.
Why?
Due to a lack of understanding about A-T, there are no effective treatments or a cure. These researchers want to discover its progression by advancing their knowledge of the disease mechanism, which can be used as a platform for possible interventions in the future. The work generated in this project could pave the way for rational drug design to stabilise ATM protein or regulate the mutant chaperone proteins, which could significantly alleviate the severity and progression of A-T disease.
How will the research be done?
The team will visualise the natural assembly pathway of ATM protein, mediated by chaperones, with a powerful electron microscope. This approach will provide critical information to understand how different mutants of ATM protein affect its stability and activity. This information will be pivotal to potentially designing potent small drug molecules to stabilise and restore the activity of ATM to decrease the gravity of the disease.
How could it make a difference in the lives of those affected by A-T?
Understanding the pathway of the ATM assembly and the role of chaperones in this process can significantly contribute to our understanding of A-T. This work could be a basis to stabilise either mutant ATM protein or mutant chaperones, which may be sufficient to slow down the disease progression in patients. It could also serve as the basis for other researchers utilising these findings to test different chemicals to push this research from the laboratory to the benefit of A-T patients.
