The First N-terminal Amino Acids of α-Synuclein Are Essential for α-Helical Structure Formation In Vitro and Membrane Binding in Yeast

摘要: α-Synuclein (α-syn), a protein implicated in Parkinson's disease, is structurally diverse. In addition to its random-coil state, α-syn can adopt an α-helical structure upon lipid membrane binding or β-sheet aggregation. We used yeast biology and vitro biochemistry detect how sequence changes alter the structural propensity of α-syn. The N-terminus protein, which adopts conformation binding, essential for yeast, variants that are more prone forming generally toxic yeast. β-Sheet inclusion formation, on other hand, appear be protective, possibly by sequestering from membrane. Surprisingly, sequential deletion residues 2 through 11 caused dramatic drop propensity, vesicle vitro, toxicity part could mimicked mutating aspartic acid at position alanine. Variants with distinct preferences, identified here reductionist approach, provide valuable tools elucidating nature forms neurons.