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 focused 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.
References
Hegde, R.S. and Keenan, R.J. (2024) A unifying model for membrane protein biogenesis. Nat. Struct. Mol. Biol., 31:1009-1017.
Yagita, Y., Zavodszky, E., Peak-Chew, S.Y., and Hegde, R.S. (2023) Mechanism of orphan subunit recognition during assembly quality control. Cell, 186:3443-3459.
Smalinskaitė, L., Kim, M.K., Lewis, A.J.O., Keenan, R.J., and Hegde, R.S. (2022) Mechanism of an intramembrane chaperone for multipass membrane proteins. Nature, 611:161-166.
Zavodszky, E., Peak-Chew, S.Y., Juszkiewicz, S., Narvaez, A. J. and Hegde, R.S. (2021) Identification of a quality control factor that monitors failures during proteasome assembly. Science, 373:998-1004.
