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首页> 外文期刊>Biochemistry >Molecular Basis for the Differences in Lipid and Lipoprotein Binding Properties of Human Apolipoproteins E3 and E4
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Molecular Basis for the Differences in Lipid and Lipoprotein Binding Properties of Human Apolipoproteins E3 and E4

机译：人载脂蛋白E3和E4脂蛋白和脂蛋白结合特性差异的分子基础

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Human apolipoprotein (apo) E4 binds preferentially to very low-density lipoproteins (VLDLs),nwhereas apoE3 binds preferentially to high-density lipoproteins (HDLs), resulting in different plasmancholesterol levels for the two isoforms. To understand the molecular basis for this effect, we engineered thenisolated apoE N-terminal domain (residues 1-191) and C-terminal domain (residues 192-299) together withna series of variants containing deletions in the C-terminal domain and assessed their lipid and lipoproteinnbinding properties. Both isoforms can bind to a phospholipid (PL)-stabilized triolein emulsion, and residuesn261-299 are primarily responsible for this activity.ApoE4 exhibits better lipid binding ability than apoE3 as anconsequence of a rearrangement involving the segment spanning residues 261-272 in the C-terminal domain.nThe strong lipid binding ability of apoE4 coupled with the VLDL particle surface being ∼60%PL-covered isnthe basis for its preference for binding VLDL rather thanHDL.ApoE4 bindsmuchmore strongly than apoE3nto VLDL but less strongly than apoE3 to HDL3, consistent with apoE-lipid interactions being relativelynunimportant for binding to HDL. The preference of apoE3 for binding to HDL3 arises because binding isnmediated primarily by interaction of the N-terminal helix bundle domain with the resident apolipoproteinsnthat cover ∼80% of the HDL3 particle surface. Thus, the selectivity in the binding of apoE3 and apoE4 tonHDL3 and VLDL is dependent upon two factors: (1) the stronger lipid binding ability of apoE4 relative to thatnof apoE3 and (2) the differences in the nature of the surfaces of VLDL and HDL3 particles, with the formernbeing largely covered with PL and the latter with protein.
机译：人载脂蛋白（apo）E4优先与极低密度脂蛋白（VLDLs）结合，而apoE3优先与高密度脂蛋白（HDLs）结合，导致两种同工型的血浆胆固醇水平不同。为了了解这种作用的分子基础，我们设计了分离的apoE N末端结构域（残基1-191）和C末端结构域（残基192-299），以及一系列在C末端结构域中含有缺失的变异体，并对其进行了评估脂质和脂蛋白结合特性。两种同工型均可与磷脂（PL）稳定的三油精乳剂结合，而残基n261-299对此活性起主要作用.ApoE4的脂类结合能力比apoE3更好，这是因为C的重排涉及跨越C-残基的残基261-272。 -apoE4的强大脂质结合能力加上VLDL颗粒表面被约60％的PL覆盖是其偏好结合VLDL而不是HDL的基础.apoE4比apoE3n与VLDL的结合力强得多，但与apoE3的HDL3结合力不强apoE-脂质相互作用对于与HDL的结合相对来说并不重要。出现apoE3与HDL3结合的偏好是因为结合主要是由N末端螺旋束结构域与覆盖约80％的HDL3颗粒表面的驻留载脂蛋白相互作用而介导的。因此，apoE3和apoE4 tonHDL3和VLDL结合的选择性取决于两个因素：（1）apoE4相对于apoE3的脂质结合能力更强；（2）VLDL和HDL3表面性质的差异颗粒，前者大部分被PL覆盖，后者被蛋白质覆盖。

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