title: N-terminal acetylation stabilizes N-terminal helicity in lipid- and micelle-bound α-synuclein and increases its affinity for physiological membranes.
abstract: The Parkinson disease protein α-synuclein is N-terminally acetylated, but most in vitro studies have been performed using unacetylated α-synuclein. Binding to lipid membranes is considered key to the still poorly understood function of α-synuclein. We report the effects of N-terminal acetylation on α-synuclein binding to lipid vesicles of different composition and curvature and to micelles composed of the detergents β-octyl-glucoside (BOG) 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 α-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, whereas the remainder of the protein remains unbound and disordered. Binding of α-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 α-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. Furthermore, the novel BOG-bound state of N-terminally acetylated α-synuclein may serve as a model of partly helical membrane-bound intermediates with a role in α-synuclein function and dysfunction.
authors: From the Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College, New York, New York 10065.
authors: Igor
authors: I
authors: Dikiy
authors: David
authors: D
authors: Eliezer
mesh_terms: D000107:Acetylation; D005960:Glucosides / Q000737:chemistry*; D006801:Humans; D008567:Membranes, Artificial; D008823:Micelles; D008958:Models, Molecular; D055550:Protein Stability; D017433:Protein Structure, Secondary; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry*; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D005960:Glucosides; D008567:Membranes, Artificial; D008823:Micelles; C497604:SNCA protein, human; D051844:alpha-Synuclein; C018619:octyl-beta-D-glucoside; D012967:Sodium Dodecyl Sulfate
keywords: Lipid-binding Protein; N-terminal Acetylation; Parkinson Disease; Post Translational Modification; Protein Aggregation; Synuclein; α-Synuclein