Zhang Meng, Charles River, Tong Huimin, Zhang Lei, Patel Mili, Wang Francis, Rames Matthew J, Ren Amy, Rye Kerry-Anne, Qiu Xiayang, Johns Douglas G, Charles M Arthur, Ren Gang
The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Centre for Vascular Research, University of New South Wales, Kensington, Sydney, NSW 2052, Australia.
Sci Rep. 2015 Mar 4;5:8741. doi: 10.1038/srep08741.
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.
胆固醇酯转运蛋白（CETP）介导胆固醇酯（CE）从具有抗动脉粥样硬化作用的高密度脂蛋白（HDL）转移至致动脉粥样硬化的低密度脂蛋白（LDL）。抑制CETP被视为一种有望提高HDL水平并进而降低心血管疾病（CVD）风险的策略。尽管CETP的晶体结构已为人所知，但关于CETP如何与HDL结合却知之甚少。在此，我们通过电子显微镜和分子动力学模拟研究了各种HDL样颗粒与CETP的相互作用。结果表明，CETP通过疏水相互作用而非蛋白质-蛋白质相互作用与HDL结合。HDL表面脂质曲率产生一个疏水环境，导致CETP疏水末端相互作用。这种相互作用独立于其他HDL成分，如载脂蛋白、胆固醇酯和甘油三酯。因此，破坏这些疏水相互作用可能是减弱CETP与HDL相互作用的一种新的治疗策略。
