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.