Salt-Induced Membrane-Bound Conformation of the NAC Domain of α-Synuclein Leads to Structural Polymorphism of Amyloid Fibrils

alpha-Synuclein (alpha S) interacts with lipid membranes in neurons to form amyloid fibrils that contribute to Parkinson's disease, and its non-amyloid-beta component domain is critical in the fibrillation. In this study, the salt (NaCl) effect on the membrane interaction and fibril formation of alpha S57-102 peptide (containing the non-amyloid-beta component domain) was characterized at the molecular level because the alpha S57-102 fibrils exhibited structural polymorphism with two morphologies (thin and thick) in the presence of NaCl but showed one morphology (thin) in the absence of NaCl. The membrane-bound conformation (before fibrillation) of alpha S57-102 had two helical regions (first and second) on the membrane regardless of salt, but the length of the first region largely shortened when NaCl was present, exposing its hydrophobic area to the solvent. The exposed region induced two distinct pathways of fibril nucleation, depending on the molar ratios of free and membrane-bound alpha S57-102: one from the association of free alpha S57-102 with membrane-bound alpha S57-102 and the other from the assembly among membrane-bound alpha S57-102. The differences mainly affected the beta-strand orientation and helical content within the fibril conformations, probably contributing to the thickness degree, leading to structural polymorphism.