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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Fibrillation precursor of superoxide dismutase 1 revealed by gradual tuning of the protein-folding equilibrium
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Fibrillation precursor of superoxide dismutase 1 revealed by gradual tuning of the protein-folding equilibrium

机译：通过逐步调节蛋白质折叠平衡揭示超氧化物歧化酶1的原纤化前体

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Although superoxide dismutase 1 (SOD1) stands out as a relatively soluble protein in vitro, it can be made to fibrillate by mechanical agitation. The mechanism of this fibrillation process is yet poorly understood, but attains considerable interest due to SODVs involvement in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). In this study, we map out the apoSODI fibrillation process from how it competes with the global folding events at increasing concentrations of urea: We determine how the fibrillation lag time (τ_(lag)) and maximum growth rate (V_(max)) depend on gradual titration of the folding equilibrium, from the native to the unfolded state. The results show that the agitation-induced fibrillation of apoSODI uses globally unfolded precursors and relies on fragmentation-assisted growth. Mutational screening and fibrillation m-values (∂ log T_(lag/∂)[urea] and ∂ log v_(max/∂)[urea]) indicate moreover that the fibrillation pathway proceeds via a diffusely bound transient complex that responds to the global physiochem-ical properties of the SOO1 sequence. Fibrillation of apoSODI, as it bifurcates from the denatured ensemble, seems thus mechanistically analogous to that of disordered peptides, save the competing folding transition to the native state. Finally, we examine by comparison with in vivo data to what extent this mode of fibrillation, originating from selective amplification of mechanically brittle aggregates by sample agitation, captures the mechanism of pathological SOD1 aggregation in ALS.
机译：尽管超氧化物歧化酶1（SOD1）在体外是一种相对可溶的蛋白质，但可以通过机械搅拌使其原纤化。这种纤颤过程的机制尚不甚清楚，但是由于SODV参与了神经退行性疾病肌萎缩性侧索硬化症（ALS），引起了人们的极大兴趣。在这项研究中，我们从尿素浓度增加的情况下与apoSODI的原纤维化过程进行了竞争，从而勾画出其过程：我们确定原纤维化滞后时间（τ_（lag））和最大增长率（V_（max））的关系从自然状态到未折叠状态逐步滴定折叠平衡。结果表明，搅动诱导的apoSODI纤颤使用了全球未折叠的前体，并依赖于碎片辅助的生长。突变筛选和原纤化m值（∂log T_（lag /∂）[尿素]和∂log v_（max /∂）[尿素]）还表明，原纤化途径通过弥散结合的瞬态复合物进行，该复合物对整体SOO1序列的理化性质。 apoSODI的原纤维化，因为它是从变性的集合中分叉的，因此在机理上与无序肽类似，但没有竞争性的折叠过渡到天然状态。最后，我们通过与体内数据进行比较来研究这种原纤维形成的模式在多大程度上源自样品搅拌引起的机械脆性聚集体的选择性扩增，从而捕获了ALS中病理性SOD1聚集的机制。

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    Lisa Lang; Martin Kurnik; Jens Danielsson; Mikael Oliveberg;

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    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden;

    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden;

    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden;

    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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