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.
- Voorhees, R. and Hegde, R. S. (2016)
Structure of the Sec61 channel opened by a signal sequence.
Science 351: 88-91
- Brown, A., Shao, S., Murray, J., Hegde, R. S., and Ramakrishnan, V. (2015)
Structural basis for stop codon recognition in eukaryotes.
Nature 524: 493-496
- Voorhees, R.M., Fernandez, I.S., Scheres, S.H.W., and Hegde, R.S. (2014)
Structure of the mammalian-Sec61 complex to 3.4 Å resolution.
Cell 157: 1632-1643
- Zhang, Z.R., Bonifacino, J.S., and Hegde, R.S. (2013)
Deubiquitinases sharpen substrate discrimination during membrane protein degradation from the ER.
Cell 154: 609-622
- Shao, S., von der Malsburg, K., and Hegde, R.S. (2013)
Listerin-dependent nascent protein ubiquitination relies on ribosome subunit dissociation.
Mol. Cell 50: 637-648
- Hessa, T., Sharma, A., Mariappan, M., Eshleman, H.D., Gutierrez, E., and Hegde, R.S. (2011)
Protein targeting and degradation are coupled for elimination of mislocalized proteins.
Nature 475: 394-397.
- Mariappan, M., Li, X., Sharma, A., Mateja, A., Keenan, R.J., and Hegde, R.S. (2010)
A ribosome-associating factor chaperones tail-anchored membrane proteins.
Nature 466: 1120-1124.
- Chakrabarti, O. and Hegde, R.S. (2009)
Functional depletion of Mahogunin by cytosolically exposed prion protein contributes to neurodegeneration.
Cell 137: 1136-1147.
- Stefanovic, S. and Hegde, R. S. (2007)
Identification of a targeting factor for post-translational membrane protein insertion into the ER.
Cell 128: 1147-1159.
- Maryann Kivlen
- Alina Guna
- Eszter Zavodszky
- Szymon Juszkiewicz
- Aaron Lewis
- Patrick Chitwood
- Zhewang Lin
- Minkyung Kim
- John O'Donnell