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 α-突触核蛋白 (αSyn) 的聚集与帕金森病 (PD) 病理学有关。αSyn 序列的中心区域包含对聚集至关重要的非淀粉样 β 组分 (NAC)。然而，NAC 侧翼区域如何调节 αSyn 聚集仍不清楚。使用生物信息学、突变和 NMR，我们确定了一个控制 αSyn 聚集的 7 个残基序列，命名为 P1（残基 36-42）。删除或替换此“主控制器”可防止体外 pH 7.5 的聚集。在较低的 pH 值下，P1 与包含 preNAC 区域（P2，残基 45-57）的序列协同作用以防止聚集。删除 P1 (ΔP1) 或同时删除 P1 和 P2 (ΔΔ) 还可以防止在秀丽隐杆线虫中的年龄依赖性 αSyn 聚集和毒性模型并通过改变脂质结合时蛋白质的构象特性来防止αSyn介导的囊泡融合。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——该区域可以针对防止疾病中的聚集。