Membrane protein biosynthesis and quality control
Cells are highly compartmentalized into numerous membrane-bound organelles. The membranes that define each organelle contain unique sets of embedded proteins that impart distinct functionalities to that organelle. How are all these different proteins selectively targeted to their correct destinations? And once they get there, how are membrane proteins inserted, folded, and assembled properly into the lipid bilayer? Defining the various pathways for membrane protein biosynthesis and understanding this machinery in molecular detail are major goals for our group.
Despite sophisticated biosynthetic pathways, sometimes things go wrong. What does the cell do when protein sorting, insertion, or folding fails? We are finding that failure is surprisingly common, and that the biosynthetic machinery is intricately linked to degradation pathways to help eliminate such mistakes. The importance of scrupulous quality control is dramatically illustrated by the consequences that result from its failure: protein aggregation, cellular dysfunction, and disease. We anticipate that our mechanistic studies of biosynthetic and quality control pathways will shed light on both a fundamental cell biological problem and the molecular basis of various diseases.
- Guna, A., Volkmar, N., Christianson, J.C. and Hegde, R.S. (2018)
The ER membrane protein complex is a transmembrane domain insertase
Science 359(6374): 470-473
- Yanagitani, K., Juszkiewicz, S., and Hegde, R.S. (2017)
UBE2O is a quality control factor for orphans of multi-protein complexes
Science 357: 472-475.
- Shao, S., Rodrigo-Brenni, M.C., Kivlen, M.H., and Hegde, R.S. (2017)
Mechanistic basis for a molecular triage reaction
Science 355(6322): 298-302.
- Juszkiewicz, S. and Hegde, R.S. (2017)
Initiation of Quality Control during Poly(A) Translation Requires Site-Specific Ribosome Ubiquitination
Mol. Cell 65(4): 743-750.
- Shao, S., Murray, J., Brown, A., Taunton, J., Ramakrishnan, V., and Hegde, R.S. (2016)
Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes
Cell 167(5): 1229-1240.
- Itakura, E., Zavodszky, E., Shao, S., Wohlever, M.L., Keenan, R.J., and Hegde, R.S. (2016)
Ubiquilins chaperone and triage mitochondrial membrane proteins for degradation
Mol. Cell 63(1): 21-33.
- Voorhees, R. and Hegde, R. S. (2016)
Structure of the Sec61 channel opened by a signal sequence.
Science 351: 88-91
- Patrick Chitwood
- Hugo Damstra
- Szymon Juszkiewicz
- Minkyung Kim
- Maryann Kivlen
- Aaron Lewis
- Zhewang Lin
- John O'Donnell
- Yuichi Yagita
- Eszter Zavodszky