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首页> 外文期刊>Journal of Molecular Biology >Local unfolding of Cu, Zn superoxide dismutase monomer determines the morphology of fibrillar aggregates
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Local unfolding of Cu, Zn superoxide dismutase monomer determines the morphology of fibrillar aggregates

机译：铜，锌超氧化物歧化酶单体的局部展开决定了原纤维聚集体的形态

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Aggregation of Cu, Zn superoxide dismutase (SOD1) is often found in amyotrophic lateral sclerosis patients. The fibrillar aggregates formed by wild type and various disease-associated mutants have recently been found to have distinct cores and morphologies. Previous computational and experimental studies of wild-type SOD1 suggest that the apo-monomer, highly aggregation prone, displays substantial local unfolding dynamics. The residual folded structure of locally unfolded apoSOD1 corresponds to peptide segments forming the aggregation core as identified by a combination of proteolysis and mass spectroscopy. Therefore, we hypothesize that the destabilization of apoSOD1 caused by various mutations leads to distinct local unfolding dynamics. The partially unfolded structure, exposing the hydrophobic core and backbone hydrogen bond donors and acceptors, is prone to aggregate. The peptide segments in the residual folded structures form the building block for aggregation, which in turn determines the morphology of the aggregates. To test this hypothesis, we apply a multiscale simulation approach to study the aggregation of three typical SOD1 variants: wild type, G37R, and I149T. Each of these SOD1 variants has distinct peptide segments forming the core structure and features different aggregate morphologies. We perform atomistic molecular dynamics simulations to study the conformational dynamics of apoSOD1 monomer and coarse-grained molecular dynamics simulations to study the aggregation of partially unfolded SOD1 monomers. Our computational studies of monomer local unfolding and the aggregation of different SOD1 variants are consistent with experiments, supporting the hypothesis of the formation of aggregation building blocks via apo-monomer local unfolding as the mechanism of SOD1 fibrillar aggregation.
机译：肌萎缩性侧索硬化症患者中经常发现铜，锌超氧化物歧化酶（SOD1）的聚集。最近发现由野生型和各种与疾病相关的突变体形成的原纤维聚集体具有不同的核心和形态。以前对野生型SOD1进行的计算和实验研究表明，高度易聚集的脱辅基单体显示出大量的局部展开动力学。局部未折叠的apoSOD1的残余折叠结构对应于形成聚集核心的肽段，如通过蛋白水解和质谱法的组合所鉴定的。因此，我们假设由各种突变引起的apoSOD1的不稳定导致了独特的局部展开动力学。暴露疏水核心和主链氢键供体和受体的部分展开结构易于聚集。残留折叠结构中的肽段形成了聚集的基础，而聚集又决定了聚集体的形态。为了验证该假设，我们采用了多尺度模拟方法来研究三种典型的SOD1变体的聚集：野生型，G37R和I149T。这些SOD1变体均具有形成核心结构的独特肽段，并具有不同的聚集形态。我们执行原子分子动力学模拟以研究apoSOD1单体的构象动力学，并进行粗粒度分子动力学模拟以研究部分未折叠的SOD1单体的聚集。我们对单体局部展开和不同SOD1变体的聚集的计算研究与实验一致，支持了通过脱辅基单体局部展开作为SOD1纤维状聚集机制形成聚集构件的假设。

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