Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein

• Published in: Nature chemical biology Vol. 8; no. 4; pp. 342 - 349
• Main Authors: Zhang, Lei, Yan, Feng, Zhang, Shengli, Lei, Dongsheng, Charles, M Arthur, Cavigiolio, Giorgio, Oda, Michael, Krauss, Ronald M, Weisgraber, Karl H, Rye, Kerry-Anne, Pownall, Henry J, Qiu, Xiayang, Ren, Gang
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 19.02.2012; Nature Publishing Group
• Subjects: 631/45/535; 631/92/287; 631/92/609; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cardiovascular diseases; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Cholesterol Ester Transfer Proteins - chemistry; Cholesterol Ester Transfer Proteins - metabolism; Cryoelectron Microscopy; Density; Humans; Hydrophobic and Hydrophilic Interactions; Lipids; Lipoproteins; Lipoproteins - chemistry; Lipoproteins - metabolism; Lipoproteins, HDL - chemistry; Lipoproteins, HDL - metabolism; Lipoproteins, LDL - chemistry; Lipoproteins, LDL - metabolism; Lipoproteins, VLDL - chemistry; Lipoproteins, VLDL - metabolism; Microscopy, Electron; Models, Molecular; Molecular Dynamics Simulation; Pores; Protein Conformation; Protein Structure, Tertiary; Proteins
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.796

Optimized negative-staining and cryo–positive staining EM reveals that human cholesteryl ester transfer protein penetrates into HDL and LDL from each distal end and potentially forms a continuous tunnel by connecting its internal series of isolated hydrophobic cavities together for cholesteryl ester transfer. Human cholesteryl ester transfer protein (CETP) mediates the net transfer of cholesteryl ester mass from atheroprotective high-density lipoproteins to atherogenic low-density lipoproteins by an unknown mechanism. Delineating this mechanism would be an important step toward the rational design of new CETP inhibitors for treating cardiovascular diseases. Using EM, single-particle image processing and molecular dynamics simulation, we discovered that CETP bridges a ternary complex with its N-terminal β-barrel domain penetrating into high-density lipoproteins and its C-terminal domain interacting with low-density lipoprotein or very-low-density lipoprotein. In our mechanistic model, the CETP lipoprotein-interacting regions, which are highly mobile, form pores that connect to a hydrophobic central cavity, thereby forming a tunnel for transfer of neutral lipids from donor to acceptor lipoproteins. These new insights into CETP transfer provide a molecular basis for analyzing mechanisms for CETP inhibition.