Dynamics of cholesterol exchange in the oxysterol binding protein family
Dynamics of cholesterol exchange in the oxysterol binding protein family
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DOI：
10.1016/j.jmb.2008.01.075
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发表时间：
2008-05-02
影响因子：
5.6
通讯作者：
Hurley, James H.
中科院分区：
文献类型：
--
作者：
Canagarajah, Bertram J.;Hummer, Gerhard;Hurley, James H.
氧固醇结合蛋白相关蛋白(ORP)家族在真核生物中的固醇转运和固醇依赖的信号转导中起着至关重要的作用。ORP家族的一个成员，酵母Osh4，在载脂蛋白和甾醇结合的状态下，其晶体结构是已知的。在结合状态下，29个残基的N末端盖区覆盖胆固醇结合隧道的开口，阻止胆固醇交换。通过对Osh4的平衡态和分子动力学(MD)模拟，研究了胆固醇交换的机理。虽然在模拟过程中大部分结构核是稳定的，但在APO平衡MD模拟中，盖子是部分打开的。螺旋α7在结晶束缚态和apo态中经历最大的构象变化，与盖子的开口是构象耦合的。α7的运动有助于在开放状态下为供体或受体膜创建对接位置。在胆固醇解离的定向MD模拟中，我们观察到覆盖胆固醇结合隧道的盖子完全打开。胆固醇被发现以一个循序渐进的过程离开结合口袋，涉及(I)打破结合口袋内的水介导的氢键和van der Waals接触，(Ii)打开覆盖结合口袋的盖子，以及(Iii)打破与口袋边缘的瞬时胆固醇接触和盖子内表面的疏水残留物。爱思唯尔有限公司出版。
The oxysterol-binding protein-related protein (ORP) family is essential to sterol transfer and sterol-dependent signal transduction in eukaryotes. The crystal structure of one ORP family member, yeast Osh4, is known in apo and sterol-bound states. In the bound state, a 29 residue N-terminal lid region covers the opening of the cholesterol-binding tunnel, preventing cholesterol exchange. Equilibrium and steered molecular dynamics (MD) simulations of Osh4 were carried out to characterize the mechanism of cholesterol exchange. While most of the structural core was stable during the simulations, the lid was partly opened in the apo equilibrium MD simulation. Helix alpha 7, which undergoes the largest conformational change in the crystallized bound and apo states, is conformationally coupled to the opening of the lid. The movement of alpha 7 helps create a docking site for donor or acceptor membranes in the open state. In the steered MD simulations of cholesterol dissociation, we observed complete opening of the lid covering the cholesterol-binding tunnel. Cholesterol was found to exit the binding pocket in a step-wise process involving (i) the breaking of water-mediated hydrogen bonds and van der Waals contacts within the binding pocket, (ii) opening of the lid covering the binding pocket, and (iii) breakage of transient cholesterol contacts with the rim of the pocket and hydrophobic residues on the interior face of the lid. Published by Elsevier Ltd.