Direct Observation of β-Barrel Intermediates in the Self-Assembly of Toxic SOD1(28-38) and Absence in Nontoxic Glycine Mutants.
Direct Observation of β-Barrel Intermediates in the Self-Assembly of Toxic SOD1(28-38) and Absence in Nontoxic Glycine Mutants.
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直接观察有毒 SOD1(28-38) 自组装中的 β-桶中间体和无毒甘氨酸突变体中的缺失
DOI：
10.1021/acs.jcim.0c01319
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发表时间：
2021-02-22
影响因子：
5.6
通讯作者：
Ding F
中科院分区：
文献类型：
--
作者：
Sun Y;Huang J;Duan X;Ding F
在淀粉样蛋白聚集的早期阶段形成的可溶性低分子量寡聚物被认为是淀粉样变性中的主要有毒物质。由于这些聚集中间体的异质性和瞬时性，寡聚体组装体与淀粉样蛋白疾病中的细胞毒性之间的结构-功能关系仍然难以捉摸。为了揭示有毒寡聚中间体的结构特征，我们使用分子动力学模拟比较了 SOD128-38（与肌萎缩侧索硬化症相关的超氧化物歧化酶 1 (SOD1) 的细胞毒性片段）及其两个无毒突变体 G33V 和 G33W 的自组装动力学和结构。据报道，SOD128-38 中的单点甘氨酸取代可消除淀粉样蛋白毒性。我们的模拟结果表明，有毒的 SOD128-38 及其无毒突变体遵循不同的聚集途径，具有不同的聚集中间体。具体来说，野生型SOD128-38最初自组装成富含无规卷曲的寡聚体，其中由明确的弯曲单层β-片层组成的纤维状聚集体通过卷曲到片层的转换和作为中间体的β-桶的形成而成核。相比之下，无毒的G33V/G33W突变体很容易组装成富含β-折叠的小寡聚物，然后彼此凝固成由两层β-折叠形成的交叉β原纤维，而不形成作为中间体的β-桶。在有毒 SOD128-38 片段组装过程中直接观察到 β-桶寡聚体，而非无毒甘氨酸取代突变体，强烈支持 β-桶作为淀粉样变性中的有毒寡聚体，可能是通过与细胞膜相互作用并形成淀粉样蛋白孔。凭借明确的结构，β-桶可能作为淀粉样蛋白相关疾病的新治疗靶点。 SOD128-38 及其 G33V/G33W 突变体的自组装动力学。野生型 SOD128-38 最初成核为非结构化寡聚物，随后构象转化为 β-折叠并形成 β-桶中间体，然后出现由弯曲单层 β-折叠组成的纳米原纤维。无毒的G33V/G33W突变体通过不同的聚集途径聚集，其中肽首先组装成小的β-折叠，这些β-折叠进一步彼此凝固成交叉β纳米原纤维，而不形成作为中间体的β-桶。
Soluble low-molecular-weight oligomers formed during the early stage of amyloid aggregation are considered the major toxic species in amyloidosis. The structure-function relationship between oligomeric assemblies and the cytotoxicity in amyloid diseases are still elusive due to the heterogeneous and transient nature of these aggregation intermediates. To uncover the structural characteristics of toxic oligomeric intermediates, we compared the self-assembly dynamics and structures of SOD128–38, a cytotoxic fragment of the superoxide dismutase 1 (SOD1) associated with the amyotrophic lateral sclerosis, with its two non-toxic mutants G33V and G33W using molecular dynamics simulations. Single-point glycine substitutions in SOD128–38 have been reported to abolish the amyloid toxicity. Our simulation results showed that the toxic SOD128–38 and its non-toxic mutants followed different aggregation pathways featuring distinct aggregation intermediates. Specifically, wild-type SOD128–38 initially self-assembled into random coil rich oligomers, among which fibrillar aggregates comprised of well-defined curved single-layer β-Sheets were nucleated via coil-to-sheet conversions and the formation of β-barrels as intermediates. In contrast, the non-toxic G33V/G33W mutants readily assembled into small β-sheet rich oligomers and then coagulated with each other into cross-β fibrils formed by two-layer β-sheets without forming β-barrels as the intermediates. The direct observation of β-barrel oligomers during the assembly of toxic SOD128–38 fragments but not the non-toxic glycine-substitution mutants strongly support β-barrels as the toxic oligomers in amyloidosis, probably via interactions with cell membrane and forming amyloid pores. With well-defined structures, the β-barrel might serve as the novel therapeutic targets against amyloid-related diseases. The self-assembly dynamics of SOD128–38 and its G33V/G33W mutants. The wild-type SOD128–38 initially nucleated into unstructured oligomers, followed by a conformational conversion into β-sheets and the formation of β-barrel intermediates before the emergence of nanofibrils comprised of curved single-layer β-sheets. The non-toxic G33V/G33W mutants aggregated via a different aggregation pathway, where the peptides first assembled into small β-sheets and these β-sheets further coagulated with each other into cross-β nanofibrils without forming β-barrels as intermediates.
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影响因子：
15
作者：
Do TD;LaPointe NE;Nelson R;Krotee P;Hayden EY;Ulrich B;Quan S;Feinstein SC;Teplow DB;Eisenberg D;Shea JE;Bowers MT
通讯作者：
Bowers MT
影响因子：
4.3
作者：
Brodie, Nicholas I.;Popov, Konstantin I.;Borchers, Christoph H.
通讯作者：
Borchers, Christoph H.
DOI：
10.1016/s1359-0278(98)00072-8
发表时间：
1998-01-01
期刊：
FOLDING & DESIGN
影响因子：
--
作者：
Dokholyan, NV;Buldyrev, SV;Shakhnovich, EI
通讯作者：
Shakhnovich, EI
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
4.6
作者：
Di Scala C;Yahi N;Boutemeur S;Flores A;Rodriguez L;Chahinian H;Fantini J
通讯作者：
Fantini J