Cholesteryl ester transfer protein (CETP) transports various lipids between lipid proteins, which can result in the net movement of cholesteryl ester from high-density lipoproteins (HDLs) to triglyceride-rich lipoproteins, such as very-low-density lipoproteins (VLDLs). The crystal structure of human CETP has an elongated boomerang shape, with a barrel on each end of the protein, a central β-sheet between the two barrels and a C-terminal extension. Four bound lipid molecules occupy a 60-Å-long continuous tunnel. Two cholesteryl esters fit the length of the tunnel, whereas two phospholipids plug each end of the tunnel. Both tunnel openings are large enough to allow lipid access, and a flexible helix and possibly also a mobile flap enhance lipid access. The N- and C-terminal tunnel openings, the flexible helix and the mobile flap have concave surfaces, which match the curvature of HDL particles, supporting the hypothesis that they make up the lipid-binding surface. Point mutants in CETP that block the middle of the tunnel abolish lipid transfer, which implies that the tunnel allows lipids to pass through its entire length rather than operating as two separate binding pockets.
ORIGINAL RESEARCH PAPER Qiu, X. et al. Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nature Struct. Mol. Biol. 14 106–113 (2007)
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