UNDERSTANDING THE PROTEASOME AND ITS EVOLUTION

Proteasomes are essential cell regulators in all eukaryotes.

They are large proteolytic complexes that break down and recycle proteins that are old, damaged, or no longer needed, that otherwise could form pathological aggregates.

They also perform the highly regulated removal of specific proteins to trigger important events including cell division.

Proteasome inhibitors are clinically used against cancer, while new inhibitors are in development against conditions ranging from inflammatory disorders to malaria. However, despite 30-years of research many fundamental aspects of proteasome function are still not fully understood.

The aims of this project are the full characterization of the structure, function, and regulation of simpler proteasomes found in archaea, with focus on Sulfolobus acidocaldarius, a model organism and the archaeal species closest to eukaryotes that can currently be routinely grown and experimentally manipulated in the laboratory.

The project is a collaboration between the groups of Professor Paula da Fonseca and Dr Nicholas Robinson at the Universities of Glasgow and Lancaster, respectively.

It will involve a wide range of experimental approaches including molecular biology, protein purification and biochemical/biophysical characterization, functional assays, structural biology primarily by cryo-EM and bioinformatics.

The outputs will elucidate the function of archaeal proteasomes and address the fundamental question: how did the intricate and highly regulated human proteasomes evolved from primitive archaeal complexes?

Because the proteasome is a critical cell regulator, understanding its fundamental working mechanisms and evolution will have a broad impact in biological sciences in general.