Calcium modulates intramolecular long-range contacts to form a polymorphic α-synuclein A53T fibril

Abstract

Human -synuclein (aSyn) is an intrinsically disordered protein, and aggregations of its amyloid fibrils are associated with Parkinsons disease (PD). Apart from familial aSyn mutations, accumulated environmental calcium exacerbates aSyn aggregation and accelerates symptoms in aging PD patients. Here, we explored the effects of Ca2+ ions on aSyn A53T, an aggregation-prone mutant variant, from disordered states to fibrillar structures. Paramagnetic nuclear magnetic resonance (NMR) revealed that binding of Ca2+ ions to the aSyn C-terminal (residues 110-140) relaxed the aSyn conformation, resulting in more aggressive fibrillogenesis. Cryo-electron microscopy structures of aSyn A53T with or without Ca2+ ion revealed substantial differences in amyloid folds and fibril assemblies. We characterized N1 (residues 61-66), N2 (residues 69-79), and N3 (residues 89-95) segments in the central non-amyloid {beta} component (NAC) crucial for forming localized structural contacts during early-step aggregation. Our work establishes the contacts governing aSyn misfolding from disordered monomer to aggregated fibril and provides insights into the structural changes elicited by Ca2+ ions.