Ubiquitin E3 ligases are central regulators of cellular proteostasis and are directly implicated in neurodegeneration. A detailed understanding of their molecular and structural mechanisms is essential for the development of targeted therapeutics. Using interdisciplinary approaches, we have identified and characterised atypical E3 ligases such as MYCBP2 and RNF213. MYCBP2 is a key regulator of axonal integrity, controlling a highly conserved axon death pathway known as Wallerian degeneration. However, how MYCBP2 activity is regulated to ensure the precise timing of axon destruction remains unclear. Importantly, the ability to block this process offers exciting therapeutic potential for a range of neurological disorders.

We are seeking a highly motivated postdoctoral researcher to join the Satpal Virdee Lab for a 3-year project focused on uncovering the cellular cues that activate MYCBP2 E3 ligase activity. Regulation of E3 ligases by metabolites is an emerging field. For example, E3 ligases can be modulated by cellular ion concentrations, and we have recently shown that the immune-related E3 ligase RNF213 is responsive to ATP levels. The project will initially investigate the effect of cellular metabolites linked to axonal integrity - such pyridine nucleotides - on MYCBP2 E3 ligase activity.

Using advanced chemical biology tools and activity-based proteomic analyses, the project will assess how MYCBP2 responds to changes in metabolite levels. While the initial focus will be on MYCBP2 and metabolites associated with neuronal function, the broader aim is to carry out ligase- and metabolite-agnostic screens to map how cellular metabolism co-regulates the ubiquitin system - advancing our molecular understanding and potentially revealing novel therapeutic strategies.

This project will use cell biology, chemical biology, and proteomics to:

• Identify the regulatory signals that control MYCBP2 E3 ligase activity
• Establish the molecular basis of small molecule-mediated regulation
• Assess the scope of E3 ligase modulation by disease-relevant metabolites

This position offers a unique opportunity to make fundamental discoveries with therapeutic relevance to neurodegeneration, infection, cancer, and cerebrovascular disease. Ideal candidates will have expertise in cell biology, proteomics, or chemical biology, and a passion for uncovering novel regulatory mechanisms.

1. Pao et al. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. (2018) Nature 556, 381-385, doi:10.1038/s41586-018-0026-1
2. Mabbitt et al. Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity. (2020) Nat Chem

MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU):

The MRC PPU is one of the world's most renowned centres for research on protein phosphorylation and ubiquitylation (http://www.ppu.mrc.ac.uk/). Many world-leading researchers in the field of signal transduction have trained within the MRC PPU. The major aims of the MRC PPU are to advance understanding of the role of protein phosphorylation and ubiquitylation in cell regulation and human disease, to facilitate the development of drugs to treat diseases caused by abnormalities in phosphorylation, to generate reagents and improve technologies. A key remit of the MRC PPU is to train the next generation of scientists who will advance our understanding in this crucial area of medical research.

School of Life Sciences (SLS):

The MRC PPU is based within the School of Life Sciences at the University of Dundee, a world-class academic institution with a reputation for the excellence of its research, its high-quality teaching and student experience, and the strong impact of its activities outside academia. With 900 staff from over 60 countries worldwide the School provides a dynamic, multi-national, collegiate and diverse environment with state-of-the-art laboratory, technology and teaching facilities.

Division of Signal Transduction Unit (DSTT):

The Division of Signal Transduction Therapy (DSTT) was established in 1998. This division operates as a unique collaboration between scientists in the MRC PPU and signalling researchers at the University of Dundee's School of Life Sciences and the pharmaceutical industry. The DSTT is widely regarded as a model for how academia should interact with industry. The DSTT operates as a simple bridging mechanism to enable our PIs working on ubiquitylation and phosphorylation to effectively interact with major pharmaceutical companies to help accelerate the early stages of drug discovery.

Your priorities will include:

• Design and implementation of biochemical enzyme assays
• Molecular biology-based molecule cloning and construct design
• Protein structure determination by crystallography or cryoEM
• Development of novel chemical biology research tools
• Maintenance of lab records comprehensive

Who we're looking for:

• Experience with the ubiquitin system
• Experience with biochemistry and cell culture methods
• Excellent communication skills
• Experience with biophysical techniques
• Experience with probe-based technologies for enzyme study

We are one of the UK's leading universities, internationally recognised for our expertise across a range of disciplines and research breakthroughs in multiple areas, including science, medicine and engineering, amongst many others. Our purpose is to transform lives, locally and globally, which we do as a community of staff (Professional Services and academic Schools), students and alumni. Professional Services directorates are key to delivering the University strategy and driving change across the University.

For further information about this position please contact Satpal Virdee (s.s.virdee@dundee.ac.uk). To find out more about MRC PPU please visit https://www.ppu.mrc.ac.uk/