The Impact of N-terminal Acetylation of alpha-Synuclein on Phospholipid Membrane Binding and Fibril Structure

A.S. Iyer, S.J. Roeters, N. Schilderink, B. Hommersom, R.M.A. Heeren, S. Woutersen, Mireille Maria Anna Elisabeth Claessens, Vinod Subramaniam

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Abstract

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.
Original languageEnglish
Pages (from-to)21110-21122
Number of pages13
JournalJournal of biological chemistry
Volume291
Issue number40
DOIs
Publication statusPublished - 2016

Keywords

  • METIS-318979
  • IR-103653

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    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