title: N-terminal acetylation of α-synuclein induces increased transient helical propensity and decreased aggregation rates in the intrinsically disordered monomer.
abstract: The conformational properties of soluble α-synuclein, the primary protein found in patients with Parkinson's disease, are thought to play a key role in the structural transition to amyloid fibrils. In this work, we report that recombinant 100% N-terminal acetylated α-synuclein purified under mild physiological conditions presents as a primarily monomeric protein, and that the N-terminal acetyl group affects the transient secondary structure and fibril assembly rates of the protein. Residue-specific NMR chemical shift analysis indicates substantial increase in transient helical propensity in the first 9 N-terminal residues, as well as smaller long-range changes in residues 28-31, 43-46, and 50-66: regions in which the three familial mutations currently known to be causative of early onset disease are found. In addition, we show that the N-terminal acetylated protein forms fibrils that are morphologically similar to those formed from nonacetylated α-synuclein, but that their growth rates are slower. Our results highlight that N-terminal acetylation does not form significant numbers of dimers, tetramers, or higher molecular weight species, but does alter the conformational distributions of monomeric α-synuclein species in regions known to be important in metal binding, in association with membranes, and in regions known to affect fibril formation rates.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Kang
authors.forename: Gina M
authors.initials: GM
authors.lastname: Moriarty
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Woods
authors.forename: Alison E
authors.initials: AE
authors.lastname: Ashcroft
authors.forename: Sheena E
authors.initials: SE
authors.lastname: Radford
authors.forename: Jean
authors.initials: J
authors.lastname: Baum
mesh_terms: D000107:Acetylation; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D013058:Mass Spectrometry; D019906:Nuclear Magnetic Resonance, Biomolecular; D010300:Parkinson Disease / Q000378:metabolism*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein