English
往期目录
新闻公告
More
化学进展 2014, Vol. 26 Issue (05): 879-888 DOI: 10.7536/PC131028 前一篇   后一篇

• 综述与评论 •

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   

  1. 1. 西安交通大学理学院应用物理系 西安 710049;
    2. The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
  • 收稿日期:2013-10-01 修回日期:2013-12-01 出版日期:2014-05-15 发布日期:2014-03-13
  • 通讯作者: 张胜利，e-mail：zhangsl@mail.xjtu.edu.cn；任罡，e-mail：gren@lbl.gov E-mail:zhangsl@mail.xjtu.edu.cn；gren@lbl.gov
  • 基金资助:

    美国能源部基础科学基金资助项目（DE-AC02-05CH11231）和美国国立卫生研究院（NIH）基金资助项目（NHLBI 1R01HL115153）；中国国家自然科学基金项目（No.11074196，11374237）资助

下载PDF ( 1006 ) 引用
导出 被引次数 ( 6 )

Structure and Function of Cholesteryl Ester Transfer Protein in Transferring Cholesteryl Ester

Lei Dongsheng1,2, Tong Huimin2, Zhang Lei2, Zhang Xing1,2, Zhang Shengli*1, Ren Gang*2   

  1. 1. Department of Applied Physics, Xi'an Jiaotong University, Xi'an 710049, China;
    2. The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
  • Received:2013-10-01 Revised:2013-12-01 Online:2014-05-15 Published:2014-03-13
  • Supported by:

    The work was supported by Basic Energy Sciences-US Department of Energy (DE-AC02-05CH11231), US National Institutes of Health (NHLBI 1R01HL115153) and the National Natural Science Foundation of China(No.11074196, 11374237)

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。

关键词： 胆固醇酯, 胆固醇酯转移蛋白, 脂蛋白, 透射电子显微镜, 分子动力学模拟, 结构柔性, 通道模型

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

Key words: cholesteryl ester, cholesteryl ester transfer protein, lipoprotein, transmission electron microscopy, molecular dynamics simulation, structural flexibility, tunnel model

中图分类号: 

()

[1] Camejo G, Waich S, Quintero G, Berrizbeitia M L, Lalaguna F. Atherosclerosis, 1976, 24(3): 341.
[2] Gordon T, Castelli W P, Hjortland M C, Kannel W B, Dawber T R. The American Journal of Medicine, 1977, 62(5): 707.
[3] Moore R B, Long J M, Matts J P, Amplatz K, Varco R L, Buchwald H. Atherosclerosis, 1979, 32(2): 101.
[4] Gordon D J, Probstfield J L, Garrison R J, Neaton J D, Castelli W P, Knoke J D, Jacobs D R Jr, Bangdiwala S, Tyroler H A. Circulation, 1989, 79(1): 8.
[5] Barter P J, Rye K A. Current Opinion in Lipidology, 2006, 17(4): 399.
[6] Rader D J. Nature Clinical Practice Cardiovascular Medicine, 2007, 4(2): 102.
[7] Assmann G, Gotto A M Jr. Circulation, 2004, 109(23 Suppl 1): Ⅲ 8.
[8] Barter P J, Brewer H B Jr, Chapman M J, Hennekens C H, Rader D J, Tall A R. Arteriosclerosis, Thrombosis, and Vascular Biology, 2003, 23(2): 160.
[9] Brown M L, Inazu A, Hesler C B, Agellon L B, Mann C, Whitlock M E, Marcel Y L, Milne R W, Koizumi J, Mabuchi H, Takeda R, Tall A R. Nature, 1989, 342(6248): 448.
[10] Marotti K R, Castle C K, Boyle T P, Lin A H, Murray R W, Melchior G W. Nature, 1993, 364(6432): 73.
[11] Morehouse L A, Sugarman E D, Bourassa P A, Sand T M, Zimetti F, Gao F, Rothblat G H, Milici A J. Journal of Lipid Research, 2007, 48(6): 1263.
[12] Rennings A J, Stalenhoef A. Expert Opinion on Investigational Drugs, 2008, 17(10): 1589.
[13] Xie L, Li J, Xie L, Bourne P E. PLoS Computational Biology, 2009, 5(5): e1000387
[14] Barter P J, Caulfield M, Eriksson M, Grundy S M, Kastelein J J, Komajda M, Lopez-Sendon J, Mosca L, Tardif J C, Waters D D, Shear C L, Revkin J H, Buhr K A, Fisher M R, Tall A R, Brewer B, Investigators I. The New England Journal of Medicine, 2007, 357(21): 2109.
[15] Schwartz G G, Olsson A G, Abt M, Ballantyne C M, Barter P J, Brumm J, Chaitman B R, Holme I M, Kallend D, Leiter L A, Leitersdorf E, McMurray J J, Mundl H, Nicholls S J, Shah P K, Tardif J C, Wright R S, Dal O I. The New England Journal of Medicine, 2012, 367(22): 2089.
[16] Qiu X, Mistry A, Ammirati M J, Chrunyk B A, Clark R W, Cong Y, Culp J S, Danley D E, Freeman T B, Geoghegan K F, Griffor M C, Hawrylik S J, Hayward C M, Hensley P, Hoth L R, Karam G A, Lira M E, Lloyd D B, McGrath K M, Stutzman-Engwall K J, Subashi A K, Subashi T A, Thompson J F, Wang I K, Zhao H, Seddon A P. Nature Structural & Molecular Biology, 2007, 14(2): 106.
[17] Zhang L, Song J, Newhouse Y, Zhang S, Weisgraber K H, Ren G. Journal of Lipid research, 2010, 51(5): 1228.
[18] Zhang L, Song J, Cavigiolio G, Ishida B Y, Zhang S, Kane J P, Weisgraber K H, Oda M N, Rye K A, Pownall H J, Ren G. Journal of Lipid research, 2011, 52(1): 175.
[19] Ren G, Rudenko G, Ludtke S J, Deisenhofer J, Chiu W, Pownall H J. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(3): 1059.
[20] Zhang L, Yan F, Zhang S, Lei D, Charles M A, Cavigiolio G, Oda M, Krauss R M, Weisgraber K H, Rye K A, Pownall H J, Qiu X, Ren G. Nat. Chem. Biol., 2012, 8(4): 342.
[21] Frank J, Radermacher M, Penczek P, Zhu J, Li Y, Ladjadj M, Leith A. Journal of Structural Biology, 1996, 116(1): 190.
[22] Ludtke S J, Baldwin P R, Chiu W. Journal of Structural Biology, 1999, 128(1): 82.
[23] Grigorieff N. Journal of Structural Biology, 2007, 157(1): 117.
[24] Scheres S H. Journal of Structural Biology, 2012, 180(3): 519.
[25] Borkotoky S, Meena C K, Khan M W, Murali A. EXCLI Journal, 2013, 12: 335.
[26] Pettersen E F, Goddard T D, Huang C C, Couch G S, Greenblatt D M, Meng E C, Ferrin T E. Journal of Computational Chemistry, 2004, 25(13): 1605.
[27] Schrodinger, LLC (2010) The Pymol Molecular Graphics System, Version 1.3r1.
[28] Sayle R. Trends in Biochemical Sciences, 1995, 20(9): 374.
[29] Humphrey W, Dalke A, Schulten K. Journal of Molecular Graphics, 1996, 14(1): 33.
[30] O'Donoghue S I, Goodsell D S, Frangakis A S, Jossinet F, Laskowski R A, Nilges M, Saibil H R, Schafferhans A, Wade R C, Westhof E, Olson A J. Nature Methods, 2010, 7(3 Suppl): S42.
[31] Zhang L, Cavigiolio G, Wang J J, Rye K A, Oda M, Ren G. Biophysical Journal, 2010, 98(3): 440a.DOI:10.1016/j.bpj.2009.12.2391.
[32] Zhang L, Kaspar A, Woodnutt G, Ren G. Biophysical Journal, 2010, 98(3): 440a.DOI:10.1016/j.bpj.2009.12.2392.
[33] Zhang L, Ren G. PloS one, 2012, 7(1): e30249
[34] Zhang L, Ren G. Biophysical Journal, 2010, 98(3): 441a.DOI:10.1016/j.bpj.2009.12.2393.
[35] Zhang L, Ren G. Biophysical Journal, 2010, 98(3): 441a.DOI:10.1016/j.bpj.2009.12.2394.
[36] Phillips J C, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel R D, Kale L, Schulten K. Journal of Computational Chemistry, 2005, 26(16): 1781.
[37] Lei D, Zhang X, Jiang S, Cai Z, Rames M J, Zhang L, Ren G, Zhang S. Proteins: Structure Function and Bioinformatics, 2013, 81(3): 415.
[38] Koivuniemi A, Vuorela T, Kovanen P T, Vattulainen I, Hyvonen M T. PLoS Computational Biology, 2012, 8(1): e1002299
[39] Hinsen K. Bioinformatics, 2008, 24(4): 521.
[40] Sinha N, Smith-Gill S J. Curr. Protein Pept. Sci., 2002, 3(6): 601.
[41] Hall J, Qiu X. Biochem. Soc. Trans., 2011, 39(4): 1000.
[42] Barter P J, Jones M E. Journal of Lipid Research, 1980, 21(2): 238.
[43] Ihm J, Quinn D M, Busch S J, Chataing B, Harmony J A K. Journal of Lipid Research, 1982, 23(9): 1328.
[44] Cheung M C, Wolf A C, Lum K D, Tollefson J H, Albers J J. Journal of Lipid Research, 1986, 27(11): 1135.
[45] Liu S, Mistry A, Reynolds J M, Lloyd D B, Griffor M C, Perry D A, Ruggeri R B, Clark R W, Qiu X. The Journal of Biological Chemistry, 2012, 287(44): 37321.
[46] Wang S, Deng L P, Milne R W, Tall A R. Journal of Biological Chemistry, 1992, 267(25): 17487.
[47] Wang S, Wang X, Deng L, Rassart E, Milne R W, Tall A R. The Journal of Biological Chemistry, 1993, 268(3): 1955.
[48] Charles M A, Kane J P. Journal of Lipid Research, 2012, 53(8): 1451.
[49] Swenson T L, Brocia R W, Tall A R. Journal of Biological Chemistry, 1988, 263(11): 5150.
[50] Wang S, Deng L P, Brown M L, Agellon L B, Tall A R. Biochemistry, 1991, 30(14): 3484.
[51] Desrumaux C, Labeur C, Verhee A, Tavernier J, Vandekerckhove J, Rosseneu M, Peelman F. The Journal of Biological Chemistry, 2001, 276(8): 5908.
[52] Weers P M, Ryan R O. Insect. Biochem. Mol. Biol., 2006, 36(4): 231.
[53] Weers P M, Narayanaswami V, Kay C M, Ryan R O. The Journal of Biological Chemistry, 1999, 274(31): 21804.
[54] Morton R E, Greene D J. Journal of Lipid Research, 2003, 44(12): 2287.
[55] Nishida H I, Arai H, Nishida T. Journal of Biological Chemistry, 1993, 268(22): 16352.
[56] Gautier T, Masson D, de Barros J P, Athias A, Gambert P, Aunis D, Metz-Boutigue M H, Lagrost L. The Journal of Biological Chemistry, 2000, 275(48): 37504.
[57] Gautier T, Masson D, Jong M C, Duverneuil L, Le Guern N, Deckert V, Pais de Barros J P, Dumont L, Bataille A, Zak Z, Jiang X C, Tall A R, Havekes L M, Lagrost L. The Journal of Biological Chemistry, 2002, 277(35): 31354.
[1] 张维佳, 邵学广, 蔡文生. 抗冻蛋白抗冻机制的分子模拟研究[J]. 化学进展, 2021, 33(10): 1797-1811.
[2] 陈淏川, 付浩浩, 邵学广, 蔡文生. 重要性采样方法与自由能计算[J]. 化学进展, 2018, 30(7): 921-931.
[3] 赵丽君, 雷鸣. 甲状腺结合前清蛋白的理论研究[J]. 化学进展, 2014, 26(01): 193-202.
[4] 常姗燕, 刘夫锋*. 三磷酸腺苷结合盒式转运体的分子模拟[J]. 化学进展, 2013, 25(07): 1208-1218.
[5] 陈景飞, 郝京诚. 表面活性剂溶液行为的粗粒化模拟[J]. 化学进展, 2012, (10): 1890-1896.
[6] 巫瑞波, 曹泽星*, 张颖凯*. 锌酶的计算模拟:挑战与最新进展[J]. 化学进展, 2012, 24(06): 1175-1184.
[7] 金海晓 严小军 朱鹏. PKA酶及其抑制剂balanol的计算化学*[J]. 化学进展, 2010, 22(05): 993-1001.
[8] 郑燕升,莫倩,孟陆丽,程谦伟. 室温离子液体的分子动力学模拟[J]. 化学进展, 2009, 21(0708): 1427-1433.
[9] 孙霞,刘庆平,郑学仿. 荧光和圆二色谱法用于低密度脂蛋白氧化的研究[J]. 化学进展, 2008, 20(11): 1761-1767.
[10] 邓平晔,张冬海,田亚峻,陈运法,丁辉. 自组装的分子动力学模拟[J]. 化学进展, 2007, 19(9): 1249-1257.
[11] 李娟,郑基深,沈非,方葛敏,郭庆祥,刘磊. 蛋白质的化学全合成*[J]. 化学进展, 2007, 19(012): 1866-1882.
[12] 刘倩,吴为辉,李人望,郑一哲,赵玉芬,李艳梅. 载脂蛋白E与阿尔兹海默病的相关研究进展*[J]. 化学进展, 2007, 19(012): 2006-2012.
[13] 蔡文生,林翼,邵学广. 团簇研究中的原子间势函数*[J]. 化学进展, 2005, 17(04): 588-596.