Project description
Identification of novel eukaryotic enzymes-targets
Post-translational protein modifications (PTMs) involve the addition of functional groups such as phosphate or sugars to proteins by specific enzymes. PTMs contribute to protein stability and significantly increase protein diversity in terms of structure and function. The EU-funded MSCA_dk_2021 project focuses on ubiquitination, a process that attaches a ubiquitin moiety to proteins. Researchers aim to investigate the presence of ubiquitin-related modifiers in yeast and human and determine their biological significance. Results will help scientists understand PTMs in eukaryotes as well as identify putative targets for the design of small molecule-based drug therapies.
Objective
Ubiquitin-related modifier 1 (Urm1) is known for its dual role as sulfur carrier protein (SCP) in tRNA thiolation and as an ubiquitin-like protein (UBL) that leads to an oxidant-induced posttranslational protein modification (PTM). We recently, managed to recapitulate the Urm1-conjugation reaction for various targets in vitro and characterize the underlying molecular principles. In most ubiquitin (Ub) and ubiquitin-like- conjugation systems, the active removal of the PTM constitutes a key feature of the regulatory mechanisms. Although, various targets of urmylation have been reported, not a single enzyme that could reverse the modification has been identified. In this project, I plan to incorporate different complementary discovery strategies to ultimately identify possible “deurmylation” enzymes in yeast and human and assess their biological significance. Foremost, I aim to uncover the guiding principles that regulate the evolutionary most ancient UBL system in eukaryotes. Hence, the expected results will not only answer one of the most intriguing questions related to Urm1, but have far-reaching consequences for our understanding of all UBL systems in eukaryotes. Last but not least, several studies hint at the critical function of Urm1 conjugation in oxidative stress response and at its direct involvement in severe human diseases. As various deubiquitylating enzymes (DUBs) are successfully developed as potent targets for small-molecule based drug therapies, the identified enzyme(s) could be well suited for novel therapeutic and diagnostic strategies.
Programme(s)
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
31-007 Krakow
Poland