HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation.
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.
The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Meng
M
Zhang
The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
River
R
Charles
The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Huimin
H
Tong
The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Lei
L
Zhang
Centre for Vascular Research, University of New South Wales, Kensington, Sydney, NSW 2052, Australia.
Mili
M
Patel
The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Francis
F
Wang
The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Matthew J
MJ
Rames
The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Amy
A
Ren
Centre for Vascular Research, University of New South Wales, Kensington, Sydney, NSW 2052, Australia.
Kerry-Anne
KA
Rye
Pfizer Inc., Groton, Connecticut 06340, USA.
Xiayang
X
Qiu
Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Douglas G
DG
Johns
School of Medicine, University of California, San Francisco, California 94115, USA.
M Arthur
MA
Charles
The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Gang
G
Ren
D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D020285:Cryoelectron Microscopy; D055032:Electron Microscope Tomography; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D021621:Imaging, Three-Dimensional; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism* / Q000648:ultrastructure; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure
C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008075:Lipoproteins, HDL; D008081:Liposomes; D008563:Membrane Lipids; D011994:Recombinant Proteins