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.