Bundles consisting of extended transmembrane segments of Vpu from HIV-1: Computer simulations and conductance measurements
Bundles consisting of extended transmembrane segments of Vpu from HIV-1: Computer simulations and conductance measurements
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DOI：
10.1021/bi025518p
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发表时间：
2002-06-11
期刊：
影响因子：
2.9
通讯作者：
Fischer, WB
中科院分区：
文献类型：
--
作者：
Cordes, FS;Tustian, AD;Fischer, WB
人类免疫缺陷病毒1型（HIV-1）基因组的一部分编码短膜蛋白Vpu，其长度为81个氨基酸。它有两个功能作用：（i）下调CD 4和（ii）支持颗粒释放。这些作用分别归因于肽的两个不同结构域，即细胞质和跨膜（TM）结构域。有人认为，增强的颗粒释放功能与Vpu的离子通道活性有关，对阳离子的偏好略高于阴离子。为了允许离子通量穿过膜，将需要Vpu以均聚物形式组装以形成功能性水填充孔。在这项研究中，分子动力学模拟被用来解决特定的氨基酸在4，5和6 TM螺旋束结构的作用。螺旋（Vpu（6-33））被延伸以包括亲水残基如Glu、Tyr和Arg（EYR基序）。我们的模拟表明，这个主题不稳定的束在其C-末端。这些碱指向孔中以形成带正电荷的环，其可以充当假定的选择性过滤器。随着螺旋数的减少，束的螺旋采用稍高的平均倾斜角。我们还认为螺旋是扭结的。对重组到脂质膜中的肽（Vpu（1-32））的电导测量表明，肽形成具有几个电导水平的离子通道。
Part of the genome of the human immunodeficiency virus type 1 (HIV-1) encodes for a short membrane protein Vpu, which has a length of 81 amino acids. It has two functional roles: (i) to downregulate CD4 and (ii) to support particle release. These roles are attributed to two distinct domains of the peptide, the cytoplasmic and transmembrane (TM) domains, respectively. It has been suggested that the enhanced particle release function is linked to the ion channel activity of Vpu, with a slight preference for cations over anions. To allow ion flux across the membrane Vpu would be required to assemble in homooligomers to form functional water-filled pores. In this study molecular dynamics simulations are used to address the role of particular amino acids in 4, 5, and 6 TM helix bundle structures. The helices (Vpu(6-33)) are extended to include hydrophilic residues such as Glu, Tyr, and Arg (EYR motif). Our simulations indicate that this motif destabilizes the bundles at their C-terminal ends. The arginines point into the pore to form a positive charged ring that could act as a putative selectivity filter. The helices of the bundles adopt slightly higher average tilt angles with decreasing number of helices. We also suggest that the helices are kinked. Conductance measurements on a peptide (Vpu(1-32)) reconstituted into lipid membranes show that the peptide forms ion channels with several conductance levels.