Development of a chemical biology toolbox for deciphering the ubiquitin code
Cells respond to external and internal stimuli by dynamically altering the functional status of existing proteins via post-translational modifications (PTMs). One of the most common and versatile PTMs in eukaryotic cells is represented by the covalent attachment of the 76-amino acid protein ubiquitin (Ub) to substrate proteins (ubiquitylation). Substrate modifications range from a single Ub moiety being attached to a protein of interest to complex polymeric Ub chains that can also contain Ub-like proteins (Ubls). Ubiquitylation plays pivotal roles in nearly all aspects of eukaryotic biology and cells dedicate an orchestrated arsenal of enzymes to install (writer proteins), translate (reader proteins) and reverse (eraser proteins) these modifications. The entirety of this complex regulatory system has been coined the Ub code. As many different human diseases, including different types of cancer and neurodegenerative diseases are being linked to dysfunctions in Ubl-related pathways, it is of utmost importance to decipher the Ub code.
Within Ubl-tool we devise a modular and interdisciplinary chemical and synthetic biology platform for studying aspects of ubiquitylation that are challenging or impossible to be addressed by more traditional technologies. We will develop innovative toolkits for generating defined Ubl architectures, including mixed, branched and hybrid Ubl chains and we will apply these tools for identifying novel reader proteins as well as for studying the functional impact of these complex types of modifications on critical cellular processes. Given its fundamental importance in eukaryotic biology, the Ub system has attracted considerable interest and promise as therapeutic target. We aim at identifying new drug targets within the Ub system by developing in cellulo activity-based probes that allow profiling activities and specificities of Ub eraser enzymes, laying thereby the foundation for the discovery of next-generation therapeutics.