SARS-CoV-2 蛋白段对结构稳定性、淀粉样蛋白生成潜能和 α-突触核蛋白聚集的不同影响

IF 2.6 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
ChemBioChem Pub Date : 2024-10-31 DOI:10.1002/cbic.202400598
Vince St Dollente Mesias, Jianing Zhang, Hongni Zhu, Xin Dai, Jixi Li, Jinqing Huang
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引用次数: 0

摘要

淀粉样变性的特点是被称为淀粉样纤维的错误折叠蛋白质的异常积累,从而导致多种临床表现。最近关于 SARS-CoV-2 蛋白段淀粉样蛋白生成的研究引起了人们对其与感染后神经退行性病变潜在联系的关注,但其机制仍不清楚。在此,我们研究了SARS-CoV-2包膜蛋白的九个残基片段(SK9)的结构、稳定性和淀粉样蛋白生成倾向,以及它们对神经元蛋白α-突触核蛋白(αSyn)聚集的影响。具体来说,SK9 野生型的氨基酸序列已从碱性和带正电荷的多肽(SFYVYSRVK),转变为近乎中性和更疏水的多肽(SAAVASAVK,标记为 SK9 var1),以及酸性和带正电荷的多肽(SFYVYSRVK,标记为 SK9 var2)。我们的研究结果表明,SK9 野生型因其无序和不稳定的性质而具有明显的淀粉样蛋白生成倾向,而 SK9 变体则具有更有序和稳定的结构,可防止淀粉样蛋白的形成。值得注意的是,SK9野生型对αSyn的聚集动力学和聚集形态有明显的影响,从而促进了αSyn聚集体的形成,并增强了抗酶降解的能力。这项研究强调了修改短肽序列以微调其特性的潜力,为了解和调节病毒诱导的淀粉样蛋白聚集提供了见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Distinct Effects of SARS-CoV-2 Protein Segments on Structural Stability, Amyloidogenic Potential, and α-Synuclein Aggregation.

Amyloidosis is characterized by the abnormal accumulation of misfolded proteins, called amyloid fibrils, leading to diverse clinical manifestations. Recent studies on the amyloidogenesis of SARS-CoV-2 protein segments have raised concerns on their potential link to post-infection neurodegeneration, however, the mechanisms remain unclear. Herein, we investigated the structure, stability, and amyloidogenic propensity of a nine-residue segment (SK9) of the SARS-CoV-2 envelope protein and their impact on neuronal protein α-synuclein (αSyn) aggregation. Specifically, the amino acid sequence of the SK9 wildtype has been modified from a basic and positively charged peptide (SFYVYSRVK), to a nearly neutral and more hydrophobic peptide (SAAVASAVK, labelled as SK9 var1), and to an acidic and negatively charged peptide (SDAVANAVK, labelled as SK9 var2). Our findings reveal that the SK9 wildtype exhibited a pronounced amyloidogenic propensity due to its disordered and unstable nature, while the SK9 variants possessed more ordered and stable structures preventing the amyloid formation. Significantly, the SK9 wildtype demonstrated distinct effect on αSyn aggregation kinetics and aggregate morphology to facilitate the formation of αSyn aggregates with enhanced resistance against enzymatic degradation. This study highlights the potential of modifying short peptide sequences to fine-tune their properties, providing insights into understanding and regulating viral-induced amyloid aggregations.

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来源期刊
ChemBioChem
ChemBioChem 生物-生化与分子生物学
CiteScore
6.10
自引率
3.10%
发文量
407
审稿时长
1 months
期刊介绍: ChemBioChem (Impact Factor 2018: 2.641) publishes important breakthroughs across all areas at the interface of chemistry and biology, including the fields of chemical biology, bioorganic chemistry, bioinorganic chemistry, synthetic biology, biocatalysis, bionanotechnology, and biomaterials. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies, and supported by the Asian Chemical Editorial Society (ACES).
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