The cholesteryl-ester transfer protein (CETP) promotes cholesteryl-ester and triglyceride transfer between lipoproteins. We evaluated the secondary structure stability of a series of small peptides derived from the C-terminus of CETP in a wide range of pH's and lipid mixtures, and studied their capability to carry out disorder-to-order secondary structure transitions dependent of lipids. We report that while a mixture of phosphatidylcholine/cholesteryl-esters forms large aggregated particles, the inclusion of a series of CETP carboxy-terminal peptides in a stable α-helix conformation, allows the formation of small homogeneous micelle-like structures. This phenomenon of lipid ordering was directly connected to secondary structural transitions at the C-terminus domain when lysophosphatidic acid and lysophosphatidylcholine lipids were employed. Circular dichroism, cosedimentation experiments, electron microscopy, as well as molecular dynamics simulations confirm this phenomenon. When purified CETP is studied, the same type of phenomenon occurs by promoting the reorganization of lipid from large to smaller particles. Our findings extend the emerging view for a novel mechanism of lipid transfer carried out by CETP, assigning its C-terminus domain the property to accomplish lipid ordering through secondary structure disorder-to-order transitions.
Described by our group a few years ago, the cholesteryl-ester transfer protein isoform (CETPI), exclusively expressed in the small intestine and present in human plasma, lacked a functional identification for a role of physiological relevance. Now, this study introduces CETPI as a new protein with the potential capability to recognise, bind and neutralise lipopolysaccharides (LPS). Peptides derived from the C-terminal domain of CETPI showed that CETPI not only might interact with several LPS serotypes but also might displace LPS bound to the surface of cells. Peptide VSAK, derived from the last 18 residues of CETPI, protected against the cytotoxic effect of LPS on macrophages. At high concentrations, when different cell types were tested in culture, it did not exhibit cytotoxicity by itself and it did prevent the expression of pro-inflammatory cytokines as well as the generation of oxidative stress conditions. In a rabbit model of septic shock, the infusion of peptide VSAK exerted a protective effect against the effects of LPS and reduced the presence of tumor necrosis factor-alpha (TNFα) in plasma. Therefore, CETPI is proposed as a new protein with the capability to advance the possibilities for better understanding and treatment of the dangerous effects of LPS in vivo.
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