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Biochemistry Seminar – Dr. Heedeok Hong: “Folding and degradation of membrane proteins”
September 25 @ 4:00 pm - 5:00 pm
Dr. Heedeok Hong
Department of Chemistry
Michigan State University
Title: “Folding and degradation of membrane proteins”
Abstract: The functional integrity of cellular proteomes is maintained by a delicate balance between protein folding and degradation. While a majority of studies on these two connected problems have focused on water-soluble proteins, it is not well understood how membrane proteins fold and how they are degraded in cells. The knowledge gap mainly stems from inherent difficulties in studying membrane protein folding in a lipid bilayer as well as the lack of an in vitro system in which detailed molecular mechanisms of degradation can be studied. To overcome the barriers, we have developed an array of new methods for studying key elements in membrane protein folding, such as thermodynamic stability, unfolding rate, compactness of the denatured state and folding cooperativity directly under native conditions. The methods are based on steric trapping which couples unfolding of a doubly-biotinylated protein to binding of monovalent streptavidin. By applying these methods to an intramembrane protease GlpG of E. coli, we elucidated a widely unraveled unfolded state, subglobal unfolding of the region encompassing the active site, and a network of cooperative and localized interactions to maintain the stability. We also successfully reconstituted the membrane protein degradation using the universally conserved membrane-integrated ATP-dependent protease FtsH as a model degradation machine in the lipid bilayers. We demonstrated that FtsH is a robust unfoldase for membrane proteins, which can accelerate unfolding of GlpG by >800 fold, and the degradation significantly depends on the substrate stability and hydrophobicity. We also show that FtsH efficiently overcomes the dual-energetic burden of substrate unfolding and membrane dislocation by efficiently utilizing ATP hydrolysis events in a highly cooperative manner. The physical principles elucidated in our study may provide general insights into membrane protein degradation mediated by ATP-dependent proteolytic systems.
Host: Jae-Hyun Cho
108 Biochemistry Building (Bldg. #1507)