The N-Terminal Repeat Domain of α-Synuclein Inhibits β-Sheet and Amyloid Fibril Formation^†

The conversion of α-synuclein into amyloid fibrils in the substantia nigra is linked to Parkinson's disease. α-Synuclein is natively unfolded in solution, but can be induced to form either α-helical or β-sheet structure depending on its concentration and the solution conditions. The N-terminus of α-synuclein comprises seven 11-amino acid repeats (XKTKEGVXXXX) which can form an amphipathic α-helix. Why seven repeats, rather than six or eight, survived the evolutionary process is not clear. To probe this question, two sequence variants of α-synuclein, one with two fewer (del2) and one with two additional (plus2) repeats, were studied. As compared to wild-type α-synuclein, the plus2 variant disfavors the formation of β-sheet-rich oligomers, including amyloid fibrils. In contrast, the truncated variant, del2, favors β-sheet and fibril formation. We propose that the repeat number in WT α-synuclein represents an evolutionary balance between the functional conformer of α-synuclein (α-helix and/or random coil) and its pathogenic β-sheet conformation. N-Terminal truncation of α-synuclein may promote pathogenesis.