HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

Scientific Reports
Meng ZhangGang Ren

Abstract

Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL.

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Citations

Jan 31, 2016·Biochimica Et Biophysica Acta·Vikram Alva, Andrei N Lupas
Mar 13, 2016·Biochimica Et Biophysica Acta·Lurong Pan, Jere P Segrest
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Jan 14, 2021·Journal of Structural Biology: X·Chris J MalajczukRicardo L Mancera

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Methods Mentioned

BETA
X-ray
electron microscopy
electron tomography

Software Mentioned

IMOD
IPET
UCSF Chimera
Visual Molecular Dynamics ( VMD )
FREALIGN
FETR
Gatan
EMAN
ctfit
SPIDER

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