Membrane protein biogenesis and quality control
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Approximately 20-25% of genes in humans encode integral membrane proteins that must be selectively targeted to and inserted into the endoplasmic reticulum (ER) membrane. These insoluble hydrophobic proteins need to transit the aqueous cytosol to the ER, where their membrane-embedded domains are guided into the lipid bilayer and folded into a functional protein. If these processes fails, the mislocalized or misfolded protein must be targeted selectively for degradation to avoid cellular dysfunction and disease. Over the past several years, our group has used cellular, biochemical, and structural approaches to understand how the critical events during membrane protein biogenesis occur with high fidelity, and how the cell recognizes failures in membrane protein biogenesis to initiate their degradation. The primary methods that are being used in the lab include biochemical reconstitution in combination with biophysical and structural analyses. Our recent efforts are increasingly focused on how multi-pass membrane proteins and membrane protein complexes are inserted and assembled. We are finding that the ER contains several poorly studied factors that facilitate this process. Our goals are to identify the full complement of membrane protein insertases and chaperones, and understand at a molecular level how they work together to ensure accurate biogenesis of the ~5500 human membrane proteins. Projects on any of these aspects of membrane protein insertion or protein quality control are tailored to suit the specific interests of individual PhD candidates.
Chitwood, P.J., Juszkiewicz, S., Guna, A., Shao, S., and Hegde, R.S. (2018)
EMC is required to initiate accurate membrane protein topogenesis.
Guna, A, Volkmar, N., Christianson, J.C. and Hegde, R.S. (2018)
The ER membrane protein complex is a transmembrane domain insertase.
Shao, S., Rodrigo-Brenni, M.C., Kivlen, M.H., and Hegde, R.S. (2017)
Mechanistic basis for a molecular triage reaction.
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, 63:21-33.
Voorhees, R.M. and Hegde, R. S. (2016)
Structure of the Sec61 channel opened by a signal sequence.