Uniqueness of CETP in transferring neutral lipids: A comparative study on lipid-carrying/binding proteins

Cholesteryl ester transfer protein (CETP) plays a central role in plasma lipid transport, facilitating the exchange of neutral lipids, such as cholesteryl esters and triglycerides, between lipoproteins. Despite the existence of several lipid-carrying/binding proteins in the family, such as lipopolysaccharide-binding protein (LBP), bacterial permeability increasing protein (BPI), and phospholipid transfer protein (PLTP), the structural and mechanistic uniqueness of CETP in neutral lipid transfer remains underexplored. Moreover, the involvement of PLTP in neutral lipid transfer is still debated, with researchers presenting conflicting mechanisms. Therefore, this study investigates the distinct structural ability of CETP in mediating neutral lipid exchange compared to other lipid-binding proteins. The study also emphasizes that simple protein modeling based on templates may not guarantee structural integrity unless validated through simulations. To achieve our objectives, we employed molecular docking, comparative molecular dynamics simulations, structural analysis, and lipid-protein interaction profiling with representative neutral lipids. In addition, protein-lipid affinities, tunnel architecture, and conformational flexibility were examined to characterize CETP's unique features and evaluate the quality of the constructed model for PLTP. The results demonstrated that a tunnel-like hydrophobic channel in CETP facilitates bidirectional neutral lipid transfer, unlike the compartmentalized binding pockets observed in other proteins. In addition, the neutral lipids' unfavorable conformational orientation was not affected in PLTP, whereas the same unfavorable conformation is changed to a favorable conformation in CETP, making only the lipid-carrying protein have the ability to transfer the neutral lipids. In conclusion, our findings highlight that the CETP is a specialized neutral lipid carrier with a unique structural mechanism distinct from typical lipid-binding proteins. This comparative insight enhances understanding of the structural plasticity of each lipid-carrying protein and the reliability of the modeled structure.