N-terminal acetylation stabilizes N-terminal helicity in lipid- and micelle-bound alpha-synuclein and increases its affinity for physiological membranes [Neurobiology]

December 12th, 2013 by Dikiy, I., Eliezer, D.

The Parkinson's disease protein alpha-synuclein is N-terminally acetylated, but most in vitro studies have been performed using unacetylated alpha-synuclein. Binding to lipid membranes is considered key to the still poorly understood function of alpha-synuclein. We report the effects of N-terminal acetylation on alpha-synuclein binding to lipid vesicles of different composition and curvature and to micelles composed of the detergents BOG (β-octyl-glucoside) and SDS. In the presence of SDS, N-terminal acetylation results in a slightly increased helicity for the N-terminal ~10 residues of the protein, likely due to the stabilization of N-terminal fraying through the formation of a helix cap motif. In the presence of BOG, a detergent used in previous isolations of helical oligomeric forms of alpha-synuclein, the N-terminally acetylated protein adopts a novel conformation, in which the N-terminal ~30 residues bind the detergent micelle in a partly helical conformation while the remainder of the protein remains unbound and disordered. Binding of alpha-synuclein to lipid vesicles with high negative charge content is essentially unaffected by N-terminal acetylation, irrespective of curvature, but binding to vesicles of lower negative charge content is increased, with stronger binding observed for vesicles with higher curvature. Thus, the naturally occurring N-terminally acetylated form of alpha-synuclein exhibits stabilized helicity at its N-terminus and increased affinity for lipid vesicles similar to synaptic vesicles, a binding target of the protein in vivo. Further, the novel BOG-bound state of N-terminally acetylated alpha-synuclein may serve as a model of partly helical membrane-bound intermediates with a role in alpha-synuclein function and dysfunction.
  • Posted in Journal of Biological Chemistry, Publications
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