Cells are amazingly organized entities. Their resident proteins, nucleic acids, and small molecules are assembled into functional modules and organized among numerous membrane-bound cellular compartments. A major area of interest in our laboratory is to understand how protein biogenesis and cellular organization is achieved with high fidelity, and how errors in these processes are recognized and rectified by the cell. We have been investigating how membrane proteins are correctly inserted into membranes, fold properly, and assemble with partners. As we learn more about these basic biosynthetic processes, we are finding that each step is imperfect. This means that aberrant protein products are constantly generated by the cell and need to be degraded efficiently to avoid various diseases including neurodegeneration. Thus, protein quality control pathways are crucial to maintaining cellular homeostasis and avoiding disease, and a second major aim is to find and investigate these quality control factors.

Current projects are focused on several aspects of normal protein biogenesis and aberrant 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:

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.

Wu, H. and Hegde, R.S. (2023) Mechanism of signal-anchor triage during early steps of membrane protein insertion. Mol. Cell, 83:961-973.

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.

Chitwood PJ, Hegde RS. (2020) An intramembrane chaperone complex facilitates membrane protein biogenesis.
Nature. 584:630-634.