Yang Mingfeng, Yordanov Boyan, Levy Yaakov, Brüschweiler Rafael, Huo Shuanghong
Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, Massachusetts 01610, USA.
Biochemistry. 2006 Oct 3;45(39):11992-2002. doi: 10.1021/bi0609927.
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.
人转甲状腺素蛋白（TTR）是一种具有淀粉样变性的蛋白质，其聚集与多种淀粉样疾病相关。以下是已提出的TTR淀粉样蛋白形成机制。TTR四聚体首先解离成天然单体，这是原纤维形成中的限速步骤。然后单体部分展开形成淀粉样变性中间体，随后经历一个自发的自组装过程。疾病相关的点突变可促进淀粉样沉积物的形成。然而，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和两个致病变体进行了分子动力学（MD）模拟。对MD生成的系综进行主坐标分析揭示了每种蛋白质的多种展开途径。仅在V30M和L55P变体的展开途径上观察到具有错位C链-环-D链基序的淀粉样变性中间体，而野生型TTR则未观察到。我们的研究表明，序列依赖性展开途径在TTR的淀粉样变性中起关键作用。侧链协同运动分析表明，“边缘链”上的致病突变破坏了微妙的侧链相关运动，这反过来可能会改变展开事件的顺序。
