Oxidized Dodecamers
In an oxidizing environment of Fe(II) and oxygen, N-terminally acetylated α-Syn forms oligomers with a substantial amount of right-hand twisted antiparallel β but no parallel β secondary structure [59]. EM images indicate that these oligomers aggregate with the smallest apparent components having a diameter of ~ 9 nm. Fig.9 illustrates a Type 2A dodecamer tri-β-barrel model of α-Syn consistent with these dimensions. The Nt and NAC domains of each monomer resemble those of the octamers of Fig. 8. However, in the dodecamer model the Sy5 and the NAC domain forms the middle β-barrel. As in some of our other models, each Ct domain forms a 4-stranded antiparallel β-sheet; but, unlike other models, these sheets form two inner β-barrels. These 24-stranded antiparallel β-barrels each have 6-fold radial symmetry and stack end-on with 2-fold perpendicular symmetry. Most of the negatively charged side-chains of the Ct-barrels either extend inwardly into the central pore where they may bind to Fe2+ ions, or are located at the ends of the barrels that are exposed to the aqueous phase or can bind to lysines in the connections between strands of the central barrel. The only outwardly oriented negatively charged side-chain near the central regions of the barrels, E130, may salt bridge to the inwardly oriented H50 in Sy5 of the middle barrel. K102 and E104 near the beginning of the first Ct strand may bind to D98 and K96 near the end of the Sy8 strand. If S/N of the inner, middle, and outer barrels are 1.0, 2/3, and 0.5, the pitches of the pleats will be about the same for all three barrels, facilitating intermeshing pleats. The theoretical gap distances between the walls of adjacent barrels should be ~ 0.75 and 0.85, consistent with the small sizes of the side-chains (primarily G, A, V, S, and T) that form the interacting pleats. This dodecamer model has six-fold radial symmetry with a relatively hydrophobic outer surface in the region of 2-fold perpendicular symmetry occupied by Sy4 strands (yellow-green). These features may facilitate aggregation into hexagonal arrays (Fig. 9c). The red circles in Fig. 9 with the diameter predicted for the dodecamer illustrate the consistency of this hypothesis with the EM images.