Proteasomes in immunity and infection
Supervisor: Professor Paula Da Fonseca, School of Molecular Biosciences
Proteasomes are large multi-subunit proteases responsible for the highly regulated degradation of most proteins in a cell. They are at the downstream end of the ubiquitin-proteasome pathway, playing a crucial role in protein homeostasis by the removal of proteins that are misfolded, damaged, or no longer needed. Moreover, proteasomes are key cell regulators by the selective removal of proteins that signal for fundamental processes including cell cycle progression, apoptosis and stress responses. In addition to the constitutive 26S proteasomes, specialised human variants include the still poorly characterised interferon-γ induced immunoproteasome and the thymoproteasome, expressed in cortical thymic epithelial cells. Proteasome inhibition is lethal due to their essential role in all cells, making them recognised drug targets against conditions such as cancer and inflammation, and we contributed to validate it as a potential antimalarial.
We use cryo-EM based approaches to investigate the intricate structure and function of proteasomes, from the full characterisation of human complexes to their targeting in parasitic diseases. The work in our lab focuses on cryo-EM and image analysis, complemented with molecular biology for the preparation and characterisation of recombinant complexes, protein purification and biochemical/biophysical characterisation, structural analysis and molecular modelling.