Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein |
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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 |
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Institution: | Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California, USA. |
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Abstract: | 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. |
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