Amyloid fibril formation of -synuclein (S) is associated with multiple neurodegenerative diseases, including Parkinson's Disease (PD). Growing evidence suggests that progression of PD is linked to cell-to-cell propagation of S fibrils, which leads to seeding of endogenous intrinsically disordered monomer via templated elongation and secondary nucleation. A molecular understanding of the seeding mechanism and driving interactions is crucial to inhibit progression of amyloid formation. Here, using relaxation-based solution NMR experiments designed to probe large complexes, we probe weak interactions of intrinsically disordered acetylated-S (Ac-S) monomers with seeding-competent Ac-S fibrils and seeding-incompetent off-pathway oligomers to identify Ac-S monomer residues at the binding interface. Under conditions that favor fibril elongation, we determine that the first 11 N-terminal residues on the monomer form a common binding site for both fibrils and off-pathway oligomers. Additionally, the presence of off-pathway oligomers within a fibril seeding environment suppresses seeded amyloid formation, as observed through thioflavin-T fluorescence experiments. This highlights that off-pathway S oligomers can act as an auto-inhibitor against S fibril elongation. Based on these data taken together with previous results, we propose a model in which Ac-S monomer recruitment to the fibril is driven by interactions between the intrinsically disordered monomer N-terminus and the intrinsically disordered flanking regions (IDR) on the fibril surface. We suggest that this monomer recruitment may play a role in the elongation of amyloid fibrils and highlight the potential of the IDRs of the fibril as important therapeutic targets against seeded amyloid formation.
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