Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom.
Nat Struct Mol Biol. 2020 Mar;27(3):249-259. doi: 10.1038/s41594-020-0384-x. Epub 2020 Mar 9.
Aggregation of human α-synuclein (αSyn) is linked to Parkinson's disease (PD) pathology. The central region of the αSyn sequence contains the non-amyloid β-component (NAC) crucial for aggregation. However, how NAC flanking regions modulate αSyn aggregation remains unclear. Using bioinformatics, mutation and NMR, we identify a 7-residue sequence, named P1 (residues 36-42), that controls αSyn aggregation. Deletion or substitution of this 'master controller' prevents aggregation at pH 7.5 in vitro. At lower pH, P1 synergises with a sequence containing the preNAC region (P2, residues 45-57) to prevent aggregation. Deleting P1 (ΔP1) or both P1 and P2 (ΔΔ) also prevents age-dependent αSyn aggregation and toxicity in C. elegans models and prevents αSyn-mediated vesicle fusion by altering the conformational properties of the protein when lipid bound. The results highlight the importance of a master-controller sequence motif that controls both αSyn aggregation and function-a region that could be targeted to prevent aggregation in disease.
人源α-突触核蛋白（αSyn）的聚集与帕金森病（PD）的病理有关。αSyn 序列的中心区域包含对聚集至关重要的非淀粉样β成分（NAC）。然而，NAC 侧翼区域如何调节 αSyn 聚集仍不清楚。我们使用生物信息学、突变和 NMR 鉴定了一个 7 个残基的序列，称为 P1（残基 36-42），它控制着 αSyn 的聚集。该“主控制器”缺失或取代可防止体外在 pH 7.5 时发生聚集。在较低的 pH 值下，P1 与包含 preNAC 区域（P2，残基 45-57）的序列协同作用，防止聚集。删除 P1（ΔP1）或同时删除 P1 和 P2（ΔΔ）也可防止 C. elegans 模型中依赖年龄的 αSyn 聚集和毒性，并通过改变蛋白与脂质结合时的构象特性来阻止 αSyn 介导的囊泡融合。这些结果强调了控制 αSyn 聚集和功能的主控制器序列基序的重要性——这一区域可能成为预防疾病中聚集的靶点。
