Completed Cells, Biochemistry & Physiology Genetics & Molecular Biology

Chemical tools for studying conventional and non-conventional modes of ubiquitylation

Funder MRC (part of UKRI)
Recipient organisation University of Dundee
Funding £2.6M
Period Mar 2018 — Mar 2024

In plain English

AI plain-English summary

Cells rely on a small protein called ubiquitin to tag other proteins for destruction, relocation, or repair—but scientists have been largely blind to which of the dozens of enzymes, known as E3s, actually attach those tags. This project provides a new set of chemical tools that can measure the activity of tens of E3s simultaneously inside a living cell, rather than one at a time. The problem is fundamental: faulty ubiquitylation drives many diseases, from cancer to neurodegeneration, yet researchers cannot easily trace which E3 is responsible for a given ubiquitin tag. Without that knowledge, developing drugs that correct the process is guesswork. The new technology fills that gap by turning a single-cell measurement into a multi-E3 readout. If successful, this tool will let researchers map the E3 activity landscape in healthy and diseased cells for the first time. That could accelerate the rational design of therapies that target specific E3s—for example, blocking an overactive E3 in cancer or boosting a sluggish one in a protein-aggregation disorder. This is fundamental science: it does not deliver a drug tomorrow, but it removes a critical bottleneck that has stalled progress in the field for years.

View original technical description
Our health and well-being are dependent on the correct functioning of the cells in our body. It is therefore imperative that we have a thorough understanding of the biochemical processes that take place within them. It is these processes that become faulty in certain diseases therefore being armed with the knowledge of their intricacies will place in a position where we can rationally develop new therapies that alleviate their symptoms of or even cure them. A cellular regulatory mechanism that affects all processes is known as protein ubiquitylation. Protein ubiquitylation involves the attachment of a small protein called ubiquitin to other proteins. This step is carried out by enzymes known as E3. Challenges with fully understanding protein ubiquitylation arise from a lack of research technologies that enable the activities of even a single E3 in a cell to be measured. Additionally, we now have strong knowledge about which proteins are tagged with ubiquitin but our ability to identify the E3 responsible is extremely difficult and new tools are urgently needed. We have recently developed some exciting and powerful technology that allows not only a single E3s activity in a cell to be measured, but the activity of tens of E3s to be measured simultaneously. This technology will revolutionise our ability to understand the roles of E3s and protein ubiquitylation in both normal and diseased cells.

View the original record at the funder ↗

Researchers

Satpal Virdee (Principal Investigator)

Related Research

Grants with similar aims, by meaning.

Activity-based Proteomics of E3 Ligases
Assessing the physiological relevance and molecular mechanisms of non-canonical ubiquitylation
Design of bioinspired tandem ubiquitin binding domains as tools to investigate the ubiquitin-modified proteome
Understanding the complexity and architecture in protein ubiquitination
Discovery and Characterisation of Undefined Ubiquitin and Ubiquitin-like E3 Ligases

Original classification

Intramural

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.