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胆固醇酯转移蛋白在胆固醇酯转移中的结构与功能
雷东升1,2, 童慧敏2, 张磊2, 张星1,2, 张胜利*1, 任罡*2
化学进展 ›› 2014, Vol. 26 ›› Issue (05) :879-888
胆固醇酯转移蛋白在胆固醇酯转移中的结构与功能
雷东升1,2, 童慧敏2, 张磊2, 张星1,2, 张胜利*1, 任罡*2
化学进展 ›› 2014, Vol. 26 ›› Issue (05) :879-888
胆固醇酯转移蛋白在胆固醇酯转移中的结构与功能
Structure and Function of Cholesteryl Ester Transfer Protein in Transferring Cholesteryl Ester
人体胆固醇酯转移蛋白（CETP）会造成胆固醇酯从高密度脂蛋白（HDL）向低密度脂蛋白（LDL）或极低密度脂蛋白（VLDL）的转移，从而增加人体患心血管疾病的危险性。了解CETP在胆固醇酯转移过程中的作用和机理，是研发新的CETP抑制剂药物以预防和治疗心血管疾病的重要基础和关键步骤。本文综述了CETP结构与功能领域研究的最新进展，详细介绍了CETP与各类脂蛋白绑定结构的高分辨透射电子显微镜研究；并结合对CETP晶体结构的分析，以及生理溶液中CETP结构与动态特征、CETP与脂滴间相互作用的分子动力学模拟研究结果，阐述并讨论了CETP脂转移机理的“通道”模型；最后对尚待解决的关键问题与未来的研究方向进行了展望，以期促进CETP功能机理的研究和抑制药物的研制。
Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Human cholesteryl esters (CEs) are naturally transferred from atheroprotective high-density lipoproteins (HDLs) to atherogenic low-density lipoproteins (LDLs) and very low-density lipoproteins (VLDLs) by cholesteryl ester transfer protein (CETP), resulting in a higher probability of CVDs. Finding out the mechanism of CETP in CE transport is an important basis for designing new CETP inhibitors for treating CVDs. This review is focused on the recent studies of CETP structure and interactions with lipoproteins. Transmission electron microscopy (TEM) studies showed that CETP not only can bind to HDL, LDL and VLDL into binary complexes, respectively, but also connects HDL and LDL or VLDL into a ternary complex via penetrating into the HDL core with its N-terminal domain and the LDL or VLDL surface with its C-terminal domain. Molecular dynamics simulations suggested that the penetrated distal ends are highly flexible under physiological conditions and when CETP contacts lipid droplets. This flexibility allows for large-scale conformational changes, and can even open pores in the distal ends. These pores and the original hydrophobic cavities within the CETP crystal structure are generally stable in physiological solution, and can even connect together into a continuous tunnel for CE transfer. Based on above results, scientists introduced and discussed the "tunnel" model for CETP-mediated lipid transfer in detail, and further suggested new interfaces of CETP for being targeted by a new generation CETP inhibitors to treat CVDs.
Contents
1 Introduction
2 Structure of CETP and lipoproteins by electron microscopy
2.1 Structure of the CETP·HDL complex by electron microscopy
2.2 3D reconstruction of CETP·HDL complex
2.3 Structure of the CETP·LDL and CETP·VLDL complexes by electron microscopy
2.4 Labeling of binding sites
2.5 Structure of the HDL·CETP·LDL and HDL·CETP·VLDL complexes by electron microscopy
2.6 Verification of CETP lipid transfer activity
3 CETP structural features by molecular dynamics simulations
3.1 Structural flexibility
3.2 Internal cavities and surface pores
3.3 Surface hydrophobicity
4 Tunnel mechanism for CETP-mediated lipid transfer
4.1 "Tunnel" model for CETP-mediated lipid transfer
4.2 CETP-lipoprotein binding
4.3 Formation of transfer tunnel
4.4 Neutral lipid transfer
5 Conclusions and outlook
胆固醇酯
cholesteryl ester
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