Cilpa-Karhu Geraldine, Jauhiainen Matti, Riekkola Marja-Liisa
Laboratory of Analytical Chemistry, Department of Chemistry, University of Helsinki, FIN-00014 Helsinki, Finland.
National Institute for Health and Welfare, Public Health Genomics Unit, Biomedicum, FIN-00251 Helsinki, Finland.
J Lipid Res. 2015 Jan;56(1):98-108. doi: 10.1194/jlr.M054288. Epub 2014 Nov 25.
Inhibition of cholesterol ester transfer protein (CETP), a protein mediating transfer of neutral lipids between lipoproteins, has been proposed as a means to elevate atheroprotective HDL subpopulations and thereby reduce atherosclerosis. However, off-target and adverse effects of the inhibition have raised doubts about the molecular mechanism of CETP-HDL interaction. Recent experimental findings have demonstrated the penetration of CETP into HDL. However, atomic level resolution of CETP penetration into HDL, a prerequisite for a better understanding of CETP functionality and HDL atheroprotection, is missing. We constructed an HDL particle that mimics the actual human HDL mass composition and investigated for the first time, by large-scale atomistic molecular dynamics, the interaction of an upright CETP with a human HDL-mimicking model. The results demonstrated how CETP can penetrate the HDL particle surface, with the formation of an opening in the N barrel domain end of CETP, put in evidence the major anchoring role of a tryptophan-rich region of this domain, and unveiled the presence of a phenylalanine barrier controlling further access of HDL-derived lipids to the tunnel of CETP. The findings reveal novel atomistic details of the CETP-HDL interaction mechanism and can provide new insight into therapeutic strategies.
胆固醇酯转运蛋白（CETP）是一种介导脂蛋白之间中性脂质转运的蛋白质，抑制该蛋白已被提议作为提高具有抗动脉粥样硬化作用的高密度脂蛋白（HDL）亚群水平从而减轻动脉粥样硬化的一种手段。然而，这种抑制作用的脱靶效应和不良反应引发了人们对CETP与HDL相互作用分子机制的质疑。最近的实验结果表明CETP能够穿透HDL。然而，对于更好地理解CETP功能和HDL抗动脉粥样硬化保护作用而言必不可少的CETP穿透HDL的原子水平分辨率尚未得到。我们构建了一种模拟实际人类HDL质量组成的HDL颗粒，并首次通过大规模原子分子动力学研究了直立状态的CETP与模拟人类HDL的模型之间的相互作用。结果表明CETP如何能够穿透HDL颗粒表面，在CETP的N桶结构域末端形成一个开口，证明了该结构域富含色氨酸区域的主要锚定作用，并揭示了存在一个苯丙氨酸屏障控制HDL衍生脂质进一步进入CETP通道。这些发现揭示了CETP与HDL相互作用机制的新原子细节，并可为治疗策略提供新的见解。
