Data associated with 'Single residue switches of aggregation in the N-terminal P1-region of alpha-synuclein'

Alpha-synuclein (αSyn) is an intrinsically disordered protein (IDP) involved in neurodegenerative disorders including Parkinson’s disease. Previous studies have shown that αSyn aggregation is controlled by interactions between the N- and C-terminal regions with the central aggregation-prone NAC-region. The closely homologous (>50% sequence identity) γ-synuclein (gSyn), by contrast, is resilient to aggregation, despite retaining the NAC-region. Here, using an alanine-scan of a 7-residue sequence in the N-terminus of αSyn previously identified as a ‘master-controller’ of aggregation (P1: residues 36-42), we identify single residues (L38, Y39 and S42) that individually control the aggregation of this IDP in vitro and in C. elegans models. Substituting residues in the P1 region of aSyn individually to those that differ in gSyn (L38M and S42A) inhibits aggregation of aSyn, while switching residues in γSyn to those in αSyn (M38L, A42S) does not change the low aggregation propensity of the γSyn variants. Using NMR-PREs and peptide binding experiments, we show how P1 synergises with residues in the NAC and C-terminal regions to initiate aggregation. Together the results demonstrate a remarkable specificity of the inter-residue interactions that control aggregation of an IDP despite their weak and transient nature.