NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils

Significance Cell-to-cell spreading of αS fibrils leads to amyloid seeding of endogenous monomer. Detailed atomic-level mechanistic understanding of the fibril seeding process of αS is essential for design of therapeutic approaches against Parkinson’s disease. In light of its complexity, this process remains ill defined at the molecular level. Using relaxation-based solution NMR experiments, we mapped a common N-terminal binding interface of the Ac-αS intrinsically disordered monomer with Ac-αS fibrils and off-pathway oligomers to elucidate critical monomer–aggregate interactions during seeded aggregation and in equilibrium with mature aggregates. From this work, we propose a paradigm in which Ac-αS monomer recruitment to the fibril is driven by interactions between the intrinsically disordered monomer N terminus and the flanking IDRs on the fibril surface.