UBICODE · Decoding the ubiquitin code

Ubiquitin (Ub) is a 76 amino acid protein that is commonly found in isopeptide linkage to a lysine residue of a target protein. This post-translational modification controls most cellular processes, including DNA repair, trafficking and protein degradation. Ubiquitin conjugation onto any of its 7 own lysine residues or onto its N-terminus results in a large number of differently linked polymers; the shape, charge and size of which determine how they interact with ubiquitin binding domains (UBDs). Binding to proteins containing such domains triggers further events that determine the fate of a Ub-tagged substrate in subsequent biochemical events in a Ub chain topology dependent manner. Malfunction of these signal transduction events contributes to the pathology of human disease. Although all Ub linkages are found in cells and all likely have specific functions, only few of them have been intensively studied so far as most linkages cannot be generated biochemically.This project will investigate how Ub linkages are recognized by UBDs to transduce cellular signals in a chain specific manner, including all linkages with all their possible topoisomers. This information will then be used to generate pharmacological modulators aimed at interfering with specific UBD-mediated signal transduction events.