Molecular basis for the differences in lipid and lipoprotein binding properties of human apolipoproteins E3 and E4.
Molecular basis for the differences in lipid and lipoprotein binding properties of human apolipoproteins E3 and E4.
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DOI：
10.1021/bi1017655
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发表时间：
2010-12-28
期刊：
影响因子：
2.9
通讯作者：
Lund-Katz S
中科院分区：
文献类型：
--
作者：
Nguyen D;Dhanasekaran P;Nickel M;Nakatani R;Saito H;Phillips MC;Lund-Katz S
人类载脂蛋白（apo）E4优先与极低密度脂蛋白（VLDL）结合，而apoE3优先与高密度脂蛋白（HDL）结合，导致两种亚型的血浆胆固醇水平不同。为了了解这种效应的分子基础，分离的apoE n端结构域（残基1-191）和c端结构域（残基192-299）以及一系列含有c端结构域缺失的变体进行了工程设计并评估了它们的脂质和脂蛋白结合特性。这两种异构体都可以与磷脂（PL）稳定的三油酸乳状液结合，残基261-299主要负责这种活性。ApoE4表现出比apoE3更强的脂质结合能力，这是c端结构域中跨越残基261-272的片段重排的结果。apoE4的高脂结合能力加上VLDL颗粒表面约60%的pl覆盖是其优先结合VLDL而不是HDL的基础。ApoE4与VLDL的结合比apoE3多，但与HDL3的结合比apoE3少，这与apoe -脂质相互作用对于与HDL的结合相对不重要是一致的。apoE3倾向于与HDL3结合，因为结合主要是通过n端螺旋束结构域与覆盖HDL3颗粒表面约80%的载脂蛋白的相互作用来介导的。因此，apoE3和apoE4与HDL3和VLDL结合的选择性取决于两个因素。1)与apoE3相比，apoE4具有更强的脂质结合能力。2) VLDL和HDL3颗粒表面性质的差异，前者大部分被PL覆盖，后者被蛋白质覆盖。
Human apolipoprotein (apo)E4 binds preferentially to very low density lipoproteins (VLDL) whereas apoE3 binds preferentially to high density lipoprotein (HDL), resulting in different plasma cholesterol levels with the two isoforms. To understand the molecular basis for this effect, the isolated apoE N-terminal domain (residues 1-191) and C-terminal domain (residues 192-299) together with a series of variants containing deletions in the C-terminal domain were engineered and assessed for their lipid and lipoprotein binding properties. Both isoforms can bind to a phospholipid (PL)-stabilized triolein emulsion and residues 261-299 are primarily responsible for this activity. ApoE4 exhibits greater lipid binding ability than apoE3 as a consequence of a rearrangement involving the segment spanning residues 261-272 in the C-terminal domain. The high lipid binding ability of apoE4 coupled with the VLDL particle surface being ~60% PL-covered is the basis for its preference to bind to VLDL rather than HDL. ApoE4 binds much more than apoE3 to VLDL but less than apoE3 to HDL3, consistent with apoE-lipid interactions being relatively unimportant for binding to HDL. The preference of apoE3 for binding to HDL3 arises because binding is mediated primarily by interaction of the N-terminal helix bundle domain with the resident apolipoproteins which cover ~80% of the HDL3 particle surface. Thus, the selectivity in apoE3 and apoE4 binding to HDL3 and VLDL is dependent upon two factors. 1) The greater lipid binding ability of apoE4 relative to apoE3. 2) The differences in the nature of the surfaces of VLDL and HDL3 particles, with the former being largely covered with PL and the latter with protein.
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影响因子：
2.9
作者：
IBDAH, JA;LUNDKATZ, S;PHILLIPS, MC
通讯作者：
PHILLIPS, MC
影响因子：
4.8
作者：
Saito, H;Dhanasekaran, P;Lund-Katz, S
通讯作者：
Lund-Katz, S
影响因子：
6.5
作者：
Getz, Godfrey S.;Reardon, Catherine A.
通讯作者：
Reardon, Catherine A.
影响因子：
4.8
作者：
Sivashanmugam, Arun;Wang, Jianjun
通讯作者：
Wang, Jianjun
DOI：
10.1073/pnas.74.3.837
发表时间：
1977-01-01
影响因子：
11.1
作者：
SHEN, BW;SCANU, AM;KEZDY, FJ
通讯作者：
KEZDY, FJ