Similarity of the non-amyloid-β component and C-terminal tail of monomeric and tetrameric alpha-synuclein with 14-3-3 sigma,Computational and Structural Biotechnology Journal

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Similarity of the non-amyloid-β component and C-terminal tail of monomeric and tetrameric alpha-synuclein with 14-3-3 sigma
Computational and Structural Biotechnology Journal ( IF 4.4 ) Pub Date : 2021-09-14 , DOI: 10.1016/j.csbj.2021.09.011
Sarah R Evans ₁ , Colista West ₂ , Judith Klein-Seetharaman _{1,

2}

Affiliation

Alpha-synuclein (αSyn) is often described as a predominantly disordered protein that has a propensity to self-assemble into toxic oligomers that are found in patients with Parkinson's and Alzheimer's diseases. αSyn's chaperone behavior and tetrameric structure are proposed to be protective against toxic oligomerization. In this paper, we extended the previously proposed similarity between αSyn and 14-3-3 proteins to the α-helical tetrameric species of αSyn in detail. 14-3-3 proteins are a family of well-folded proteins with seven human isoforms, and function in signal transduction and as molecular chaperones. We investigated protein homology, using sequence alignment, amyloid, and disorder prediction, as well as three-dimensional visualization and protein-interaction networks. Our results show sequence homology and structural similarity between the aggregation-prone non-amyloid-β component (NAC) residues Val-52 to Gly-111 in αSyn and 14-3-3 sigma residues Leu-12 to Gly-78. We identified an additional region of sequence homology in the C-terminal region of αSyn (residues Ser-129 to Asp-135) and a C-terminal loop of 14-3-3 between helix αH and αI (residues Ser-209 to Asp-215). This data indicates αSyn shares conserved domain architecture with small heat shock proteins. We show predicted regions of high amyloidogenic propensity and intrinsic structural disorder in αSyn coincide with amyloidogenic and disordered predictions for 14-3-3 proteins. The homology in the NAC region aligns with residues involved in dimer- and tetramerization of the non-amyloidogenic 14-3-3 proteins. Because 14-3-3 proteins are generally not prone to misfolding, our results lend further support to the hypothesis that the NAC region is critical to the assembly of αSyn into the non-toxic tetrameric state.

中文翻译：

单体和四聚体 α-突触核蛋白的非淀粉样蛋白-β 成分和 C 末端尾部与 14-3-3 sigma 的相似性

α-突触核蛋白 (αSyn) 通常被描述为一种主要无序的蛋白质，具有自组装成有毒寡聚体的倾向，这种寡聚体存在于帕金森病和阿尔茨海默病患者中。 αSyn 的分子伴侣行为和四聚体结构被认为可以防止有毒的寡聚化。在本文中，我们将先前提出的 αSyn 和 14-3-3 蛋白之间的相似性详细扩展到 αSyn 的 α 螺旋四聚体。 14-3-3 蛋白是一个折叠良好的蛋白家族，具有七种人类亚型，在信号转导和分子伴侣中发挥作用。我们利用序列比对、淀粉样蛋白和紊乱预测以及三维可视化和蛋白质相互作用网络研究了蛋白质同源性。我们的结果显示了 αSyn 中易于聚集的非淀粉样蛋白-β 成分 (NAC) 残基 Val-52 至 Gly-111 与 14-3-3 σ 残基 Leu-12 至 Gly-78 之间的序列同源性和结构相似性。我们在αSyn的C端区域（残基Ser-129到Asp-135）中鉴定了一个额外的序列同源性区域，以及螺旋αH和αI之间的14-3-3的C端环（残基Ser-209到Asp） -215）。该数据表明 αSyn 与小型热休克蛋白共享保守结构域结构。我们显示 αSyn 中高淀粉样蛋白生成倾向和内在结构紊乱的预测区域与 14-3-3 蛋白的淀粉样蛋白生成和无序预测一致。 NAC 区域中的同源性与参与非淀粉样蛋白 14-3-3 蛋白的二聚体和四聚化的残基对齐。由于 14-3-3 蛋白通常不易发生错误折叠，因此我们的结果进一步支持了以下假设：NAC 区域对于 αSyn 组装成无毒四聚体状态至关重要。

更新日期：2021-09-14

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