Graphene Quantum Dots Modulate Stress Granule Assembly and Prevent Abnormal Phase Transition of Fused in Sarcoma Protein,ACS Nano

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Graphene Quantum Dots Modulate Stress Granule Assembly and Prevent Abnormal Phase Transition of Fused in Sarcoma Protein
ACS Nano ( IF 15.8 ) Pub Date : 2023-05-19 , DOI: 10.1021/acsnano.3c00001
Hong Zhang ₁ , Jinge Gu ₂ , Yiling Zhang ₁ , Huazhang Guo ₃ , Shengnan Zhang ₂ , Jie Song ₁ , Cong Liu ₂ , Liang Wang ₃ , Dan Li _{4,

5,

6} , Bin Dai ₁

Affiliation

Protein liquid–liquid phase separation (LLPS) plays a crucial role in mediating dynamic assembly of different membraneless organelles such as stress granules (SGs). Dysregulation of dynamic protein LLPS leads to aberrant phase transition and amyloid aggregation which is closely associated with neurodegenerative diseases. In this study, we found that three types of graphene quantum dots (GQDs) exhibit potent activity in preventing SG formation and promoting SG disassembly. We next demonstrate that GQDs can directly interact with the SGs-containing protein fused in sarcoma (FUS), inhibit and reverse FUS LLPS, and prevent its abnormal phase transition. Moreover, GQDs display superior activity in preventing amyloid aggregation of FUS and disaggregating preformed FUS fibrils. Mechanistic study further demonstrates that GQDs with different edge-site exhibit distinct binding affinity to FUS monomers and fibrils, which accounts for their distinct activities in modulating FUS LLPS and fibrillation. Our work reveals the potent capability of GQDs in modulating SG assembly, protein LLPS, and fibrillation and sheds light on rational design of GQDs as effective modulators of protein LLPS for therapeutics application.

中文翻译：

石墨烯量子点调节应力颗粒组装并防止融合在肉瘤蛋白中的异常相变

蛋白质液-液相分离 (LLPS) 在调节不同无膜细胞器（如应激颗粒 (SG)）的动态组装中起着至关重要的作用。动态蛋白 LLPS 的失调导致异常相变和淀粉样蛋白聚集，这与神经退行性疾病密切相关。在这项研究中，我们发现三种类型的石墨烯量子点 (GQD) 在防止 SG 形成和促进 SG 分解方面表现出强大的活性。我们接下来证明 GQD 可以直接与肉瘤融合蛋白 (FUS) 相互作用，抑制和逆转 FUS LLPS，并防止其异常相变。此外，GQD 在防止 FUS 的淀粉样蛋白聚集和解聚预形成的 FUS 原纤维方面表现出优异的活性。机理研究进一步表明，具有不同边缘位点的 GQD 对 FUS 单体和原纤维表现出不同的结合亲和力，这解释了它们在调节 FUS LLPS 和原纤维化方面的不同活性。我们的工作揭示了 GQD 在调节 SG 组装、蛋白质 LLPS 和原纤维化方面的强大能力，并阐明了 GQD 作为蛋白质 LLPS 有效调节剂用于治疗应用的合理设计。

更新日期：2023-05-19

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