TYPE 2 Models
α-helical and α-β-barrel tetramers
Fig. 5a shows an EM image of an α-Syn tetramer composed primarily of
partially occupied α-helices [41]. This image is shown to emphasize
the importance of tetramers and to suggest that helical structures may
represent a starting point from which oligomers with β-secondary
structures develop. This type of conformational change may initiate
transitions from predominately α-helical monomers with intra-monomer
backbone H-bonds to parallel β-sheets of fibrils with inter-monomer
backbone H-bonds.
The transition from primarily α-helical to antiparallel β oligomers may
involve oligomers with both types of secondary structures. A relatively
common protein structural motif is a TIM barrel in which the secondary
structure alternates between α-helices and β-strands, with the β-strands
forming a relatively hydrophobic 8-stranded parallel core β-barrel that
is surrounded by eight relatively amphipathic α-helices [54]. The
model we suggest here differs in that the Nt domain forms an α-helical
hairpin and the NAC domain forms a β-hairpin. Once four monomers
aggregate to form tetramers, the more hydrophobic NAC domains may
migrate to the core where they form an 8-stranded antiparallel β-barrel
that is surrounded by amphipathic α-helices. The charged side-chains of
the Nt helices would be oriented outwardly where they are exposed to the
aqueous phase and can interact with oppositely charged side-chains of
adjacent α-helices, and their hydrophobic surfaces on the opposite side
of the helices would interact with the NAC β-barrel (Fig. 5 b-e). The
α-Syn and β-Syn proteins diverged long ago [55]; nonetheless, in the
Nt domain only six side-chains differ between the two families; these
are all on the polar faces of the helices (circled in purple in Fig. 5).
The NAC domain is less conserved; the first five residues of Sy6 differ,
the Sy7 (boxed in red) putative β-hairpin is deleted in β-Syn, and three
residues of Sy8 differ. However, there are stretches of four (GAVV) and
six (IAAATG) consecutive identical small apolar or ambivalent (T)
residues in Sy6 and Sy8 that are spatially adjacent at the center of the
model (green background in Fig. 5d): alanines comprise the central pleat
and alanine, glycine, and valine comprise the two adjacent pleats. Some
of these conserved apolar residues should interact with conserved apolar
residues on the back sides to the Nt helices. The γ-Syn sequence has
more differences, but the overall conservation pattern is similar. There
are 13 differences in the Nt domain, but only two are on the back side
of the helices. Only 16 of 34 residues in the NAC domain are identical
in the two sequences, but three and two consecutive residues are
identical in the mid regions of Sy6 and Sy8.