Human α-synuclein (αS) has been shown to be N terminally acetylated in its physiological state. This modification is proposed to modulate the function and aggregation of αS into amyloid fibrils. Using bacterially expressed acetylated-αS (NTAc-αS) and endogenous αS (Endo-αS) from human erythrocytes, we show that N-terminal acetylation has little impact on αS binding to anionic membranes and thus likely not relevant for regulating membrane affinity. N-terminal acetylation does have an effect on αS aggregation, resulting in a narrower distribution of the aggregation lag times and rates. 2D-IR spectra show that acetylation changes the secondary structure of αS in fibrils. This difference may arise from the slightly higher helical propensity of acetylated-αS in solution leading to a more homogenous fibril population with different fibril structure than non-acetylated αS. We speculate that N-terminal acetylation imposes conformational restraints on N-terminal residues in αS, thus predisposing αS toward specific interactions with other binding partners or alternatively decrease nonspecific interactions.
Iyer, A. S., Roeters, S. J., Schilderink, N., Hommersom, B., Heeren, R. M. A., Woutersen, S., ... Subramaniam, V. (2016). The Impact of N-terminal Acetylation of alpha-Synuclein on Phospholipid Membrane Binding and Fibril Structure. Journal of biological chemistry, 291(40), 21110-21122. https://doi.org/10.1074/jbc.M116.726612