Membrane-induced initial structure of α-synuclein control its amyloidogenesis on model membranes.

Amyloid fibrillation causes serious neurodegenerative diseases and amyloidosis; however, the detailed mechanisms by which the structural states of precursor proteins in a lipid membrane-associated environment contribute to amyloidogenesis still remains to be elucidated. We examined the relationship between structural states of intrinsically-disordered wild-type and mutant α-synuclein (αSN) and amyloidogenesis on two-types of model membranes. Highly-unstructured wild-type αSN (αSN _WT ) and a C-terminally-truncated mutant lacking negative charges (αSN ₁₀₃ ) formed amyloid fibrils on both types of membranes, the model membrane mimicking presynaptic vesicles (Mimic membrane) and the model membrane of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC membrane). Unstructured αSN _WT and αSN ₁₀₃ both bound to Mimic membranes in a helical conformation with similar binding affinity. Promotion and then inhibition of amyloidogenesis of αSN _WT were observed as the concentration of Mimic lipids increased. We explain this by the two-state binding model: at lower lipid concentrations, binding of αSN _WT to membranes enhances amyloidogenicity by increasing the local concentration of membrane-bound αSN and so promoting amyloid nucleation; at higher lipid concentrations, membrane-bound αSN _WT is actually in a sense diluted by increasing the number of model membranes, which blocks amyloid fibrillation due to an insufficient bound population for productive nucleation. Meanwhile, αSN ₁₀₃ formed amyloid fibrils over the whole concentration of Mimic lipids used here without inhibition, revealing the importance of helical structures for binding affinity and negatively charged unstructured C-terminal region for modulating amyloidogenesis. We propose that membrane binding-induced initial conformations of αSN, its overall charge states, and the population of membrane-bound αSN are key determinants of amyloidogenesis on membranes.
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