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Structural Commonalities Determined by Physicochemical Principles in the Complex Polymorphism of the Amyloid State of Proteins.
Biochemical Journal ( IF 4.4 ) Pub Date : 2024-12-18 , DOI: 10.1042/bcj20240602
Silvia Errico,Giulia Fani,Salvador Ventura,Joost Schymkowitz,Frederic Rousseau,Antonio Trovato,Michele Vendruscolo,Francesco Bemporad,Fabrizio Chiti

Advances in solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryoEM) have revealed the polymorphic nature of the amyloid state of proteins. Given the association of amyloid with protein misfolding disorders, it is important to understand the principles underlying this polymorphism. To address this problem, we combined computational tools to predict the specific regions of the sequence forming the β-spine of amyloid fibrils with the availability of 30, 83 and 24 amyloid structures deposited in the Protein Data Bank (PDB) and Amyloid Atlas (AA) for the amyloid β (Aβ) peptide, α-synuclein (αS), and the 4R isoforms of tau, associated with Alzheimer's disease, Parkinson's disease, and various tauopathies, respectively. This approach enabled a statistical analysis of sequences forming β-sheet regions in amyloid polymorphs. We computed for any given sequence residue n the fraction of PDB/AA structures in which that residue adopts a β-sheet conformation (Fβ(n)) to generate an experimental, structure-based profile of Fβ(n) vs n, which represents the β-conformational preference of any residue in the amyloid state. The peaks in the respective Fβ(n) profiles of the three proteins, corresponding to sequence regions adopting more frequently the β-sheet structural core in the various fibrillar structures, align very well with the peaks identified with five predictive algorithms (ZYGGREGATOR, TANGO, PASTA, AGGRESCAN, WALTZ). These results indicate that, despite amyloid polymorphism, sequence regions most often forming the structural core of amyloid have high hydrophobicity, high intrinsic β-sheet propensity and low electrostatic charge across the sequence, as rationalised and predicted by the algorithms.

中文翻译:


由物理化学原理确定的蛋白质淀粉样蛋白状态的复杂多态性的结构共性。



固体核磁共振 (ssNMR) 波谱和低温电子显微镜 (cryoEM) 的进展揭示了蛋白质淀粉样蛋白状态的多态性。鉴于淀粉样蛋白与蛋白质错误折叠疾病的关联,了解这种多态性背后的原理很重要。为了解决这个问题,我们结合了计算工具来预测形成淀粉样蛋白原纤维 β-spine 的序列的特定区域,蛋白质数据库 (PDB) 和淀粉样蛋白图谱 (AA) 中存储了 30、83 和 24 个淀粉样蛋白结构,用于淀粉样蛋白 β (Aβ) 肽、α-突触核蛋白 (αS) 和 tau 的 4R 亚型, 分别与阿尔茨海默病、帕金森病和各种 tau 蛋白病相关。这种方法能够对淀粉样蛋白多晶型物中形成β片区域的序列进行统计分析。我们计算了任何给定序列残基 n 的 PDB/AA 结构的分数,其中该残基采用 β 折叠构象 (Fβ(n)) 来生成 Fβ(n) 与 n 的实验性、基于结构的轮廓,这代表了淀粉样蛋白状态下任何残基的 β 构象偏好。三种蛋白质各自 Fβ(n) 谱中的峰,对应于在各种纤维结构中更频繁地采用 β 层结构核心的序列区域,与用五种预测算法(ZYGGREGATOR、TANGO、PASTA、AGGRESCAN、WALTZ)鉴定的峰非常吻合。这些结果表明,尽管淀粉样蛋白多态性,但最常形成淀粉样蛋白结构核心的序列区域在整个序列中具有高疏水性、高内在β片倾向和低静电荷,正如算法合理化和预测的那样。
更新日期:2024-12-18
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