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.