Local unfolding of Cu, Zn superoxide dismutase monomer determines the morphology of fibrillar aggregates.
Local unfolding of Cu, Zn superoxide dismutase monomer determines the morphology of fibrillar aggregates.
复制标题
DOI：
10.1016/j.jmb.2011.12.029
复制
发表时间：
2012-08-24
影响因子：
5.6
通讯作者：
Dokholyan, Nikolay V.
中科院分区：
文献类型：
--
作者：
Ding, Feng;Furukawa, Yoshiaki;Nukina, Nobuyuki;Dokholyan, Nikolay V.
关键词：
肌萎缩侧索硬化症(ALS)患者常出现铜锌超氧化物歧化酶(SOD1)聚集现象。最近发现，野生型和各种疾病相关突变体形成的纤维状聚集体具有不同的核心和形态。先前对野生型SOD1的计算和实验研究表明，这种高度易于聚集的脱辅基单体表现出大量的局部展开动力学。局部展开的apoSOD1的残馀折叠结构对应于通过蛋白质分解和质谱学相结合鉴定的形成聚集核心的多肽片段。因此，我们假设apoSOD1由各种突变引起的不稳定导致了不同的局部展开动力学。部分展开的结构暴露出疏水核心和主干氢键供体和受体，容易聚集。残存折叠结构中的多肽片段形成聚集的“积木”，进而决定聚集的形态。为了验证这一假设，我们应用多尺度模拟方法研究了三个典型的SOD1变体：Wildtype、G37R和I149T的聚集。这些SOD1变异体中的每一个都有形成核心结构的不同的多肽片段，并具有不同的聚集形态。我们用原子分子动力学模拟来研究apoSOD1单体的构象动力学，用粗粒分子动力学模拟来研究部分未折叠的SOD1单体的聚集。我们对单体局部展开和不同SOD1异构体聚集的计算研究与实验一致，支持了SOD1纤维聚集机制是通过非单体局部展开形成聚集“积木”的假说。
Aggregation of Cu, Zn Superoxide Dismutase (SOD1) is often found in Amyotrophic Lateral Sclerosis (ALS) patients. The fibrillar aggregates formed by wildtype and various disease-associated mutants have recently been found to have distinct cores and morphologies. Previous computational and experimental studies of wildtype 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: wildtype, 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.
登录
查看更多内容
影响因子：
3.4
作者：
Ding, F;Dokholyan, NV;Shakhnovich, EI
通讯作者：
Shakhnovich, EI
影响因子：
46.9
作者：
通讯作者：
--
DOI：
10.1016/j.str.2008.03.013
发表时间：
2008-07
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Ding F;Tsao D;Nie H;Dokholyan NV
通讯作者：
Dokholyan NV
影响因子：
5.6
作者：
Kayatekin, Can;Zitzewitz, Jill A.;Matthews, C. Robert
通讯作者：
Matthews, C. Robert
DOI：
10.1038/nsb935
发表时间：
2003-06-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Elam, JS;Taylor, AB;Hart, PJ
通讯作者：
Hart, PJ