Chemical biology tools to study crosstalk between cell metabolism and protein degradation

In order to maintain homeostasis in response to environmental changes such as nutrient availability, eukaryotic cells have evolved intricate mechanisms to quickly increase or decrease the activity of fundamental processes such as gene expression, protein expression and degradation. Indeed, several metabolites act as cofactors for important cellular enzymes that regulate e.g. chromatin state and serve as templates for posttranslational modifications flagging proteins for proteolysis via the ubiquitin-proteasome system. Consequently, the identification of metabolites and complementary binding domains has broadened our understanding of human physiology and contributed to the development of new medicines to treat malignant and inflammatory disease. The aim of this project is to systematically map protein-metabolite interactions on a proteome-wide scale by combining the development of specific metabolite-inspired affinity reagents with unbiased approaches such as thermal profiling to dissect metabolite signalling in the context of protein degradation pathways in various cell types. Applicants will have the opportunity to take advantage of a unique combination of synthetic organic chemistry and cell biology techniques to identify new potential drug targets and develop first-in-class ligands for key regulators of protein homeostasis.