title: Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein.
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.
authors.affiliation: Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.forename: Shengli
authors.initials: S
authors.lastname: Zhang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Lei
authors.forename: M Arthur
authors.initials: MA
authors.lastname: Charles
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cavigiolio
authors.forename: Michael
authors.initials: M
authors.lastname: Oda
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: Karl H
authors.initials: KH
authors.lastname: Weisgraber
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Pownall
authors.forename: Xiayang
authors.initials: X
authors.lastname: Qiu
authors.forename: Gang
authors.initials: G
authors.lastname: Ren
mesh_terms: D053480:Cholesterol Ester Transfer Proteins / Q000737:chemistry* / Q000378:metabolism*; D020285:Cryoelectron Microscopy; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008074:Lipoproteins / Q000737:chemistry* / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000737:chemistry / Q000378:metabolism; D008854:Microscopy, Electron; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL