Alpha synuclein: Primary Structure

a-Syn is one of the most abundant ‘‘natively unfolded’’(intrinsically disordered) proteins that likely have different morphologies, including protofibrils, oligomers, and fibrils. Under physiologic conditions, a-syn has little or no ordered structure and possesses noteworthy conformational plasticity. The primary structure of a-syn is characterized as follows: (a) Residues 1-60 constitute the N-terminal domain
encompassing the conserved imperfect hexameric repeats (KTKEGV) and includes three missense mutations associated with early-onset familial PD (A30P, E46K, and A53T). The conserved 11-residue (XKTKEGVXXXA, X = any amino acid)repeat forms amphipathic secondary a-helical structures on binding to acidic phospholipid membranes, typical of the lipid-binding domains of apolipoproteins; (b) the central region (residues 61 to 95) is composed of an extremely hydrophobic, highly aggregation-prone NAC (nonamyloid component) sequence; and (c) the hydrophilic C-terminal region consists of highly acidic residues glutamic and aspartic acid, as well as proline, and is responsible for chaperone function.