Abstract The 20S proteasome, the catalytic core particle of 26S proteasome, degrades a wide range of intracellular proteins, which is essential for many cellular processes. Herein, we have found that the 20S proteasome activity is either up- or down-regulated by introducing gold nanoclusters (AuNCs) coated with nine peptide tails in two different forms, AuNC(−) and AuNC(+), each encoding five consecutive negatively or positively charged amino acids. Molecular dynamics simulations reveal that AuNC(−) and AuNC(+) bind to different surfaces of the 20S proteasome, and respectively facilitate or hinder the opening of the central gate of 20S proteasome for substrate access to the internal active site for protein degradation. Furthermore, the addition of AuNC(-) induces protective effects in a cell model of Parkinson’s disease, by up-regulating the proteasome activity under the condition of reduced ATP production, and enhancing the degradation of overexpressed α-synuclein, thereby attenuating the loss of cell viability. Our findings suggest the potential application of gold nanoclusters for treating neurodegenerative diseases.

中文翻译：

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带电金纳米团簇调节蛋白酶体活性：对神经退行性疾病的影响

摘要 20S 蛋白酶体是 26S 蛋白酶体的催化核心颗粒，可降解多种细胞内蛋白质，这对许多细胞过程至关重要。在此，我们发现通过引入涂有 9 个肽尾的金纳米团簇 (AuNC) 以两种不同的形式，AuNC(-) 和 AuNC(+)，分别编码五个连续的负离子，20S 蛋白酶体的活性被上调或下调。或带正电荷的氨基酸。分子动力学模拟表明，AuNC(-) 和 AuNC(+) 与 20S 蛋白酶体的不同表面结合，分别促进或阻碍 20S 蛋白酶体中心门的打开，以便底物进入蛋白质降解的内部活性位点。此外，添加 AuNC(-) 可在帕金森病细胞模型中诱导保护作用，通过在ATP产生减少的条件下上调蛋白酶体活性，并增强过表达的α-突触核蛋白的降解，从而减轻细胞活力的损失。我们的研究结果表明金纳米团簇在治疗神经退行性疾病方面的潜在应用。