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首页> 外文期刊>Journal of Molecular Biology >Identification of a conserved aggregation-prone intermediate state in the folding pathways of Spc-SH3 amyloidogenic variants
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Identification of a conserved aggregation-prone intermediate state in the folding pathways of Spc-SH3 amyloidogenic variants

机译：在Spc-SH3淀粉样变性变体的折叠途径中保守的倾向于聚集的中间状态的鉴定

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摘要

We compared the folding pathways of selected mutational variants of the α-spectrin SH3 domain (Spc-SH3) by using a continuum model that combines a full atomistic protein representation with the Gō potential. Experimental data show that the N47G mutant shows very little tendency to aggregate while the N47A and triple mutant D48G(2Y) are both amyloidogenic, with the latter being clearly more aggregation prone. We identified a strikingly similar native-like folding intermediate across the three mutants, in which strand β 1 is totally unstructured and more than half of the major hydrophobic core residues are highly solvent exposed. Results from extensive docking simulations show that the ability of the intermediates to dimerize is largely driven by strand β 1 and is consistent with the in vitro aggregation behavior reported for the corresponding mutants. They further suggest that residues 44 and 53, which are key players in the nucleation-condensation mechanism of folding, are also important triggers of the aggregation process.
机译：我们通过使用结合了完整的原子蛋白表示和Gō势的连续模型，比较了α-spectrinSH3结构域（Spc-SH3）的选定突变变体的折叠途径。实验数据表明，N47G突变体几乎没有聚集趋势，而N47A和三重突变体D48G（2Y）都是淀粉样蛋白，而后者明显更倾向于聚集。我们在这三个突变体中发现了惊人相似的天然样折叠中间体，其中链β1完全无结构，并且一半以上的主要疏水性核心残基高度暴露于溶剂中。大量对接模拟的结果表明，中间体二聚化的能力在很大程度上受链β1的驱动，并且与相应突变体报道的体外聚集行为一致。他们进一步表明，残基44和53是折叠成核-缩合机制的关键参与者，也是引发聚集过程的重要诱因。

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