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首页> 外文期刊>Biochemistry >Complexation of NAC-Derived Peptide Ligands with the C-Terminus of alpha-Synuclein Accelerates Its Aggregation
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Complexation of NAC-Derived Peptide Ligands with the C-Terminus of alpha-Synuclein Accelerates Its Aggregation

机译：NAC衍生的肽配体与α-突触核蛋白的C-末端的络合加速了其聚集

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Aggregation of alpha-synuclein (alpha-Syn) into neurotoxic oligomers and amyloid fibrils is suggested to be the pathogenic mechanism for Parkinson's disease (PD). Recent studies'have indicated that oligomeric species of alpha-Syn are more cytotoxic than their mature fibrillar counterparts, which are responsible for dopaminergic neuronal cell death in PD. Therefore, the effective therapeutic strategies for tackling aggregation-associated diseases would be either to prevent aggregation or to modulate the aggregation process to minimize the formation of toxic oligomers during aggregation. In this work, we showed that arginine-substituted alpha-Syn ligands, based on the most aggregation-prone sequence of alpha-Syn, accelerate the protein aggregation in a concentration-dependent manner. To elucidate the mechanism by which Arg-substituted peptides could modulate alpha-Syn aggregation kinetics, we performed surface plasmon resonance (SPR) spectroscopy, nuclear magnetic resonance (NMR) studies, and all-atom molecular dynamics (MD) simulation. The SPR analysis showed a high binding potency of these peptides with alpha-Syn but one that was nonspecific in nature. The two-dimensional NMR studies suggest that a large stretch within the C-terminus of alpha-Syn displays a chemical shift perturbation upon interacting with Arg-substituted peptides, indicating C-terminal residues of alpha-Syn might be responsible for this class of peptide binding. This is further supported by MD simulation studies in which the Arg-substituted peptide showed the strongest interaction with the C-terminus of alpha-Syn. Overall, our results suggest that the binding of Arg-substituted ligands to the highly acidic C-terminus of alpha-Syn leads to reduced charge density and flexibility, resulting in accelerated aggregation kinetics. This may be a potentially useful strategy while designing peptides, which act as alpha-Syn aggregation modulators.
机译：α-突触核蛋白（α-SYN）聚集成神经毒性低聚物和淀粉样蛋白原纤维，是帕金森病（PD）的致病机制。最近的研究表明，α-SYN的低聚物种比其成熟的原纤维对应物更具细胞毒性，这对PD中的多巴胺能神经元细胞死亡负责。因此，解决聚集相关疾病的有效治疗策略是为了防止聚集或调节聚集过程，以最小化聚集期间有毒低聚物的形成。在这项工作中，我们表明，基于α-SYN的最常见易发序列的精氨酸取代的α-SYN配体，以浓度依赖性方式加速蛋白质聚集。为了阐明Arg取代肽可以调节α-SYN聚集动力学的机制，我们进行了表面等离子体共振（SPR）光谱，核磁共振（NMR）研究和全原子分子动力学（MD）模拟。 SPR分析表明，这些肽的高结合效力与α-SYN，但本质上是非特异性的。二维NMR研究表明，α-SYN的C-末端内的大规模伸展在与阿尔替代肽相互作用时显示出化学换档扰动，表明α-SYN的C末端残留可能是这类肽的负责捆绑。通过MD模拟研究进一步支持，其中Arg取代的肽显示出与α-SYN的C末端的最强相互作用。总体而言，我们的研究结果表明，Arg-取代配体与α-SYN的高度酸性C末端的结合导致降低电荷密度和柔韧性，导致加速的聚集动力学。这可能是设计肽的潜在有用的策略，其充当α-SYN聚合调制器。

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  • 来源
    《Biochemistry》 |2018年第5期|共14页
  • 作者

    Jha Narendra Nath; Ranganathan Srivastav; Kumar Rakesh; Mehra Surabhi; Panigrahi Rajlaxmi; Navalkar Ambuja; Ghosh Dhiman; Kumar Ashutosh; Padinhateeri Ranjith; Maji Samir K.;

  • 作者单位

    Indian Inst Technol Dept Biosci &

    Bioengn Bombay 400076 Maharashtra India;

    Indian Inst Technol Dept Biosci &

    Bioengn Bombay 400076 Maharashtra India;

    Indian Inst Technol Dept Biosci &

    Bioengn Bombay 400076 Maharashtra India;

    Indian Inst Technol Dept Biosci &

    Bioengn Bombay 400076 Maharashtra India;

    Indian Inst Technol Dept Biosci &

    Bioengn Bombay 400076 Maharashtra India;

    Indian Inst Technol Dept Biosci &

    Bioengn Bombay 400076 Maharashtra India;

    Indian Inst Technol Dept Biosci &

    Bioengn Bombay 400076 Maharashtra India;

    Indian Inst Technol Dept Biosci &

    Bioengn Bombay 400076 Maharashtra India;

    Indian Inst Technol Dept Biosci &

    Bioengn Bombay 400076 Maharashtra India;

    Indian Inst Technol Dept Biosci &

    Bioengn Bombay 400076 Maharashtra India;

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  • 正文语种 eng
  • 中图分类 生物化学;
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