Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules

Abstract

Cholesteryl ester transfer protein (CETP) shuttles various lipids between lipoproteins, resulting in the net transfer of cholesteryl esters from atheroprotective, high-density lipoproteins (HDL) to atherogenic, lower-density species. Inhibition of CETP raises HDL cholesterol and may potentially be used to treat cardiovascular disease. Here we describe the structure of CETP at 2.2-A resolution, revealing a 60-A-long tunnel filled with two hydrophobic cholesteryl esters and plugged by an amphiphilic phosphatidylcholine at each end. The two tunnel openings are large enough to allow lipid access, which is aided by a flexible helix and possibly also by a mobile flap. The curvature of the concave surface of CETP matches the radius of curvature of HDL particles, and potential conformational changes may occur to accommodate larger lipoprotein particles. Point mutations blocking the middle of the tunnel abolish lipid-transfer activities, suggesting that neutral lipids pass through this continuous tunnel.

Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects

“…The position of L261R is predicted to be located at surface of the neck region of the CETP tunnel. Y375S, F265R and F270R are CETP mutagenesis mutants which are not secreted, and these structural positions are located at surfaces in the neck region and they are in the vicinity of L261R position [3]. Probably, these surfaces of the neck region would be essential for CETP protein secretion.…”

“…It forms the boomerang shape and has a long tunnel with two openings, and phospholipids are plugging as sides of the tunnel openings and two of CE or TG bind in the tunnel [3]. The level of CETP activity varies in animal species, and mice, rats and dogs have almost no CETP activity because functional CETP gene is lost in their evolutionary process [4].…”

Structure of HDL: Particle Subclasses and Molecular Components

“…In the circulation, CETP shuttles between HDL and apoB-containing lipoproteins and facilitates the bidirectional transfer of cholesteryl esters and triglycerides between them. The structure of CETP includes a hydrophobic tunnel filled with two cholesteryl ester molecules and plugged by an amphiphilic phosphatidylcholine (PC) molecule at each end (Qiu et al 2007). Such interactions additionally endow CETP with PC transfer activity.…”

Cholesteryl ester transfer protein: The controversial relation to atherosclerosis and emerging new biological roles

“…In the middle of this decade, the first large scale clinical trial using a CETP inhibitor, torcetrapib, was interrupted earlier than anticipated due to high mortality rates (16). In 2007, about 40 years after the discovery of CETP activity, its molecular structure was finally resolved (17). This finding promises to be a milestone since it allows for the elucidation of the CETP mechanism of action and more refined drug design.…”