Protein quality control involves the regulation of functional protein concentration at an optimal level in cells. To achieve this cellular need, a variety of biomolecular phenomena including protein synthesis, protein folding, chaperone action, and protein turnover are coordinated and balanced. While many studies on protein quality control focus on water-soluble proteins, it is not well understood how the quality control of membrane proteins is maintained. However, this question has been challenging to address due to difficulties in establishing tractable model systems in the lipid bilayer environment. This dissertation aims to answer two specific problems in membrane biology: 1) How does the lipid bilayer influence the folding and cooperativity of membrane proteins? 2) How do the intrinsic folding properties of membrane proteins influence their susceptibility to degradation? Using the intramembrane protease GlpG as a model, I find that, compared to micelles, the lipid bilayer enhances the stability of the protein by facilitating residue burial in the protein interior and strengthening the cooperative interaction network. Also, I find that conformational stability is not a major determinant of degradation rates of membrane proteins, and rather, the hydrophobicity of transmembrane segments or the conformational distribution of denatured state ensembles impact more. This finding suggests that the rate-limiting step of FtsH-mediated degradation of membrane proteins is not substrate denaturation but the dislocation of the hydrophobic transmembrane segments from the membrane to water. My studies will contribute to the fundamental understanding of the lipid bilayer as a solvent mediating folding, function, and quality control of membrane proteins.
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