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

Aditya Iyer, Steven J Roeters, Nathalie Schilderink, Bob Hommersom, Ron M A Heeren, Sander Woutersen, Mireille M A E 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 - 30 Sep 2016

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    • Journal Article

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