Cells are amazingly organised entities. Their resident proteins, nucleic acids and small molecules are assembled into functional modules and segregated among numerous membrane-bound cellular compartments. A major goal of modern cell biology is to understand how protein biogenesis and cellular organisation is achieved with high fidelity, and how errors in these processes are recognised and rectified by the cell. Our group is currently addressing two related problems in this area. First, we seek to understand how mammalian cells correctly produce their ~5000 membrane proteins, insert them into the lipid bilayer, fold them and assemble them into complexes. Examples include GPCRs, transporters, receptors, ion channels and others. Producing membrane proteins is a fundamental task faced by all cells that have ever lived, and achieving it accurately is crucial for health and homeostasis.
Second, we want to determine how cells identify and degrade unassembled subunits of protein complexes, an inevitable consequence of imbalanced gene expression. Eliminating such “orphan” proteins is crucial for avoiding the accumulation of aberrant proteins and loss of cellular homeostasis. Indeed, deficiencies in eliminating orphan proteins leads to neurodegeneration. Conversely, cancer cells have highly imbalanced gene expression and are therefore highly dependent on the pathways of orphan degradation.
Current projects are focussed on several aspects of membrane protein biogenesis and orphan protein degradation that range from mechanistic studies in vitro, to analysis of its importance in cells. We employ a range of techniques, including biochemical reconstitution, molecular genetic studies in cultured cells and structural analysis. Projects on any of these or other aspects of protein biogenesis or cellular quality control are possible. The choice of specific project(s) will therefore be made in consultation with the PhD candidate to suit the individual’s conceptual and methodological interests.