American scientists from the Lawrence National Laboratory in Berkeley finally found out how the protein - carrier of cholesterol esters (CETP) provides a transfer of cholesterol from "good" high density lipoproteins (HDLs ) to "bad" low density lipoproteins (LDLs). This opens up new avenues for the design of safer and more effective CETP inhibitors of a new generation that could prevent the development of cardiovascular diseases.
(1) CETP penetrates the HDL. (2) Formation of pores at both ends of the CETP. (3) The pores mate with the cavity in the CETP, forming a channel for the transfer of cholesterol, (4) which leads to a decrease in HDL in size. (Illustration Gang Ren / Berkeley Lab.)
He leads the research team, which first recorded the structural representation of CETP interactions with HDLs and LDLs, Gan Ren, an expert in electron microscopy and a material science scientist from the Lawrence Lab in Berkeley. The structural maps and structural analysis obtained by her confirm the hypothesis that cholesterol is transferred from HDLs to LDLs through a tunnel passing through the center of the CETP molecule.
According to the researchers, CETP is a small (53 kDa) asymmetric molecule resembling a banana with a wedge-shaped N-terminal domain and a spherical C-terminal domain. Scientists have discovered that the N-terminal penetrates HDL, while the C-terminal interacts with LDL. Structural analysis allowed them to put forward a hypothesis that this triple interaction is capable of generating an effort that twists the terminals, forming pores at both ends of the CETP. The pores, in turn, mate with the central cavity in the CETP molecule, forming a tunnel, which serves as a kind of aqueduct for the movement of cholesterol from HDL.
The results of the work are published in the journal Nature Chemical Biology.
Cardiovascular diseases (mainly atherosclerosis) remain the main cause of early death in the US and the world. Elevated levels of LDL-cholesterol and (or) decreased - HDL-cholesterol in the blood plasma, for their part, are the main risk factors for the development of heart failure. That is why the creation of effective CETP inhibitors has become a very popular pharmacological approach to the treatment of cardiovascular diseases. But, despite the highest clinical interest in CETP, to this day, little has been known about the mechanism of the cholesterol transfer between lipoproteins. It remained unclear even exactly how CETP binds to these lipoproteins.
Mr. Ren explains that it is very difficult to study the mechanisms of CETP using standard structural and imaging methods, since interaction with CETP changes the size, shape and even composition of lipoproteins, especially HDL. His team was successful thanks to the negative contrast electron microscopy technique, whose optimized protocol was developed by the scientist and his colleagues to depict how CETP interacts with the HDL and LDL spherical particles. A special technique for processing the resulting images allowed the creation of a three-dimensional reconstruction of the CETP molecule and the CETP-HDL adduct. Modeling the dynamics of the system made it possible to calculate the molecular mobility of CETP and predict the changes associated with cholesterol transfer.
According to Gan Jen, the model created in general outlines the mechanism by which the transfer of cholesterol occurs. This is really an important step towards the development of a rational design of CETP-inhibitors of a new generation for the treatment of cardiovascular diseases.