The sequence-dependent unfolding pathway plays a critical role in the amyloidogenicity of transthyretin
The sequence-dependent unfolding pathway plays a critical role in the amyloidogenicity of transthyretin
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DOI：
10.1021/bi0609927
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发表时间：
2006-10-03
期刊：
影响因子：
2.9
通讯作者：
Huo, Shuanghong
中科院分区：
文献类型：
--
作者：
Yang, Mingfeng;Yordanov, Boyan;Huo, Shuanghong
人甲状腺素运载蛋白（TTR）是一种淀粉样蛋白，其聚集与几种类型的淀粉样疾病有关。已经提出了TTR淀粉样蛋白形成的以下机制。TTR四聚体首先解离成天然单体，这是原纤维形成的限速步骤。然后单体物质部分解折叠形成淀粉样蛋白生成中间体，其随后经历下坡自组装过程。淀粉样蛋白存款可通过疾病相关的点突变来促进。然而，在野生型和疾病相关变体的晶体结构之间仅观察到细微的结构差异。为了研究单点突变如何影响TTR单体的有效能量景观，对野生型TTR和两种致病性变体进行分子动力学（MD）模拟。主坐标分析MD产生的合奏揭示了多种展开途径，每种蛋白质。具有错位C链-环-D链基序的淀粉样蛋白生成中间体仅在V30 M和L55 P变体的展开途径上观察到，而对于野生型TTR则没有。我们的研究表明，序列依赖性去折叠途径在TTR的淀粉样变性中起着至关重要的作用。侧链协同运动的分析表明，致病突变的“边缘链”破坏微妙的侧链相关的运动，这反过来可能会改变序列的展开事件。
Human transthyretin (TTR) is an amyloidogenic protein whose aggregation is associated with several types of amyloid diseases. The following mechanism of TTR amyloid formation has been proposed. TTR tetramer at first dissociates into native monomers, which is the rate-limiting step in fibril formation. The monomeric species then partially unfold to form amyloidogenic intermediates that subsequently undergo a downhill self-assembly process. The amyloid deposit can be facilitated by disease-associated point mutations. However, only subtle structural differences were observed between the crystal structures of the wild type and the disease-associated variants. To investigate how single-point mutations influence the effective energy landscapes of TTR monomers, molecular dynamics ( MD) simulations were performed on wild-type TTR and two pathogenic variants. Principal coordinate analysis on MD-generated ensembles has revealed multiple unfolding pathways for each protein. Amyloidogenic intermediates with the dislocated C strand-loop-D strand motif were observed only on the unfolding pathways of V30M and L55P variants and not for wild-type TTR. Our study suggests that the sequence-dependent unfolding pathway plays a crucial role in the amyloidogenicity of TTR. Analyses of side chain concerted motions indicate that pathogenic mutations on "edge strands" disrupt the delicate side chain correlated motions, which in turn may alter the sequence of unfolding events.