A structural biology approach to understand IMPDH2 rod-ring structures in Embryonic Stem Cells
Not stated
- Funding
- Self-Funded PhD Students Only
- Application deadline
- Year-round applications
About the project
About the Project IMPDH2 is a critical enzyme responsible for the rate limiting step of purine nucleotide biosynthesis. In naïve pluripotent stem cells, it forms large rod-ring structures (RRs) which are hypothesised to control the enzyme’s output when the pool of guanine nucleotides is in high demand. However, whether IMPDH2 interacts with other proteins in these structures is not well defined, and neither is their function during early embryogenesis. We want to understand how IMPDH2 RRs form, whether there are other proteins localised to these structures, and whether they are critical for IMPDH2 stability and aggregation. Objectives: We will take a combined structural bioinformatic and cell biological approach to undertake the following: 1. Use computational approaches to predict whether other proteins interact with IMPDH2. 2. Generate ESC lines carrying mutations in key IMPDH2 residues that regulate RR formation and assess the consequences of these mutations on potential binding partners 3. Determine the functional impact of disrupting IMPDH2’s interaction with binding partners on pluripotency and lineage-specific differentiation. Experimental Approach: We will apply predictive tools such as AlphaFold 3 to model IMPDH2 interactions in silico, followed by validation using super-resolution microscopy and advanced ESC culture techniques. Novelty: This project has the potential to understand how IMPDH2 RRs during early mammalian development, providing new insight into how signalling pathways integrate with metabolic and gene-regulatory networks to control pluripotency and differentiation. Student Development and Training: The student will benefit from co-supervision from the primary and secondary supervisors, gaining training in cutting-edge deep learning-based structural bioinformatics methods, developmental signalling, 3D gastruloid culture, stem cell biology, advanced imaging, and biochemical approaches. Regular supervisory meetings and integration across the two groups will provide robust support, while day-to-day guidance will come from postdocs and peers. Both supervisors have proven records of mentoring early-career researchers and supporting colleagues into diverse scientific and non-scientific career paths. The student will be encouraged to participate in DiMeN training, present at international meetings, and engage with the supervisors’ collaborative networks. This will ensure they develop independence, technical versatility, and a competitive skill set for careers in academia, industry, or translational research. Supervisory team: Primary Supervisor: David Turner - www.gastruloids.com https://www.liverpool.ac.uk/people/david-turner Secondary Supervisor: Dan Rigden - https://www.liverpool.ac.uk/people/daniel-rigden Please email your CV and cover letter to the primary supervisor, Dr David Turner, in the first instance david.turner@liverpool.ac.uk