β-Barrel topology of Alzheimer's β-amyloid ion channels.
β-Barrel topology of Alzheimer's β-amyloid ion channels.
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DOI：
10.1016/j.jmb.2010.10.025
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发表时间：
2010-12-17
影响因子：
5.6
通讯作者：
Nussinov R
中科院分区：
文献类型：
--
作者：
Jang H;Arce FT;Ramachandran S;Capone R;Lal R;Nussinov R
新的证据支持阿尔茨海默病的离子通道机制，即小分子β-淀粉样蛋白(A-β)寡聚体插入细胞膜，形成有毒的离子通道，破坏细胞离子稳态。基于固体核磁共振的溶液中淀粉样低聚物的数据表明，它们由双层β-Sheet组成，其中每个单体折叠成β-Strand-Turn-β-链，单体相互堆叠。在膜中，Aβ多肽被认为是β类结构。原子力显微镜对膜中A-β齐聚物成像的实验结构数据揭示了异质通道的形态。以前，我们在非倾斜的组织中模拟通道，平行于跨膜法线。在这里，我们建立了一个类似β桶的组织模型。β-桶在跨膜毒素孔中很常见，通常由形成孔的单体链组成，以单层β-片状组织，具有反平行的β-链和右旋螺旋。我们的显式溶剂分子动力学模拟了一系列通道大小和多态转折，并与原子力显微镜图像尺寸进行了比较，支持β-Barrel通道组织。与跨膜β桶不同的是，在跨膜β桶中，单体折叠成圆形的β-Sheet，通过连接环稳定反平行的β-链，而这些A-β桶由多聚链组成，形成具有平行β-链的双CSP-Sheet，其中每个单体的链通过旋转连接。尽管Aβ桶采用右手β-Sheet扭转，但桶仍然分解成不同的、松散连接的亚单位，这与原子力显微镜图像和之前的建模很好地一致。亚基看起来像是流动的，允许不受监管的离子流动，因此是有毒的。
Emerging evidence supports the ion channel mechanism for Alzheimer’s disease pathophysiology wherein small β-amyloid (Aβ) oligomers insert into the cell membrane, forming toxic ion channels and destabilizing the cellular ionic homeostasis. Solid-state NMR-based data of amyloid oligomers in solution indicate that they consist of a double-layered β-sheets where each monomer folds into β-strand–turn–β-strand and the monomers are stacked atop each other. In the membrane, Aβ peptides are proposed to be β-type structures. Experimental structural data available from atomic force microscopy (AFM) imaging of Aβ oligomers in membranes reveal heterogeneous channel morphologies. Previously, we modeled the channels in a non-tilted organization, parallel with the cross-membrane normal. Here, we modeled a β-barrel-like organization. β-Barrels are common in transmembrane toxin pores, typically consisting of a monomeric chain forming a pore, organized in a single-layered β-sheet with antiparallel β-strands and a right-handed twist. Our explicit solvent molecular dynamics simulations of a range of channel sizes and polymorphic turns and comparisons of these with AFM image dimensions support a β-barrel channel organization. Different from the transmembrane β-barrels where the monomers are folded into a circular β-sheet with antiparallel β-strands stabilized by the connecting loops, these Aβ barrels consist of multimeric chains forming double β-sheets with parallel β-strands, where the strands of each monomer are connected by a turn. Although the Aβ barrels adopt the right-handed β-sheet twist, the barrels still break into heterogeneous, loosely attached subunits, in good agreement with AFM images and previous modeling. The subunits appear mobile, allowing unregulated, hence toxic, ion flux.
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影响因子：
4.3
作者：
ARISPE, N;POLLARD, HB;ROJAS, E
通讯作者：
ROJAS, E
DOI：
10.1073/pnas.0607815103
发表时间：
2006-10-31
影响因子：
11.1
作者：
Ferguson, Neil;Becker, Johanna;Fersht, Alan R.
通讯作者：
Fersht, Alan R.
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P
影响因子：
15
作者：
Chimon, S;Ishii, Y
通讯作者：
Ishii, Y
影响因子：
5.6
作者：
de Planque, Maurits R. R.;Raussens, Vincent;Watts, Anthony
通讯作者：
Watts, Anthony