We investigate how cellular signalling pathways are regulated by post-translational modifications. The two main types of post-translational modifications are phosphorylation and ubiquitination. Ubiquitination regulates nearly all cellular functions and is achieved by attachment of the small protein ubiquitin to a wide variety of substrates.
Ubiquitin regulatory versatility is achieved through the formation of a ubiquitin code comprised of at least eight different types of ubiquitin chains: Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, Lys63 and Met1. Dedicated ‘writers’ assemble the code, ‘readers’ decipher the code and ‘erasers’ reverse the code
These eight ubiquitin chain types are known to exist in cells and have defined cellular roles, the most characterised being Lys48-linked ubiquitin chains that serve as a signal for protein degradation. Other chain types are emerging as important regulators of cell signalling pathways. The importance of defined ubiquitin chains is underscored in inflammatory signalling pathways where defects in the ability to synthesise Met1 ubiquitin chains is causative of several human auto-inflammatory and immuno-deficiency diseases.
Using an integrated structural, biochemical and biophysical approach, our lab aims to understand, at the mechanistic level, how the ubiquitin code is regulated and how the ubiquitin signal controls inflammatory signalling pathways.