N-terminal acetylation of ?-synuclein induces increased transient helical propensity and decreased aggregation rates in the intrinsically disordered monomer.

ABSTRACT: The conformational properties of soluble ?-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 ?-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 ?-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 ?-synuclein species in regions known to be important in metal binding, in association with membranes, and in regions known to affect fibril formation rates.

SUBMITTER: Kang L 

PROVIDER: S-EPMC3403430 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature