Figure 14. Images and models of α-Syn and β-Syn stacked lipoprotein discs. (a) Two sizes of α-Syn stacked pairs obtained by image averaging. (b) Individual images of relatively long stacks for both α- and β-Syn. (Images modified from original EM images of Eichmann et al. [19]). (c) Side views of schematics of our models. The darkly shaded regions in the middle of and between the cylinders represent lipid-filled regions. The gray cylinders represent concentric β-barrels formed by the Nt and NAC domains from two discs; the magenta cylinders represent 32-stranded β-barrels formed by interlocking Ct domains from adjacent stacks. (d) A schematic model for the central stack illustrating variations of the numbers of octamers in adjacent discs of the stack above. (e) Wedge cross-sections representations of the Nt-NAC barrel regions of the octamers within a disc. The checkered regions inside and between the octamers represent lipid alkyl chains.
We considered several models for the basic components of the α- and β-Syn discs. The Type 2P octamer model illustrated in Figs. 15 and Appendix A1 were the most consistent with dimensions obtained from the EM images. Sy2,4,6 form an inner 24-stranded β-barrel and Sy1,3,5,8 form a 32-stranded outer β-barrel. Four-stranded Ct β-sheets from adjacent octamers interlock to form a 32-stranded antiparallel β-barrel that connects octamers. The pore through the inner β-barrel is lined with apolar side-chains and is ~ 3 nm in diameter. This region is proposed to surround sphingolipid alkyl chains. The entrances to this pore are surrounded by positively charged lysines of the signature connectors. These may interact with negatively charged phosphate moieties of the lipid head-groups. The negatively-charged Ct β-barrel is proposed to surround the positively charged portions of the sphingolipid head-groups. The calculated distance between discs based on these model is ~ 7.6 nm, about the same as observed in the micrographs.
The next challenge was to account for the lightly-shaded vertical columns that are ~3.5 nm apart in the image-averaged discs (Fig. 14a). The Type 2P octamer structure has four-fold radial symmetry and 2-fold perpendicular symmetry. Adjacent octamers within the same disc likely form a square lattice in which all contacts are identical and occur at regions of 2-fold symmetry (Fig. 14 e). In an aqueous environment these contacts would likely occur in the most hydrophobic regions; i.e., between antiparallel pairs of Sy8 strands. However, in a hydrophobic environment the contacts would likely occur between more polar segments; i.e., at antiparallel pairs of Sy1 strands and adjacent Sy3 strands. The latter case would occur if lipids occupy the regions between the octamers, as illustrated in Fig. 14e. Positively charged lysines at the ends of the Sy5-8 strands could interact with negatively charged components of inter-octamer lipid head groups, and negatively charged side-chains on the exterior of the Ct β-barrels could interact with positively charged components of these lipids. This arrangement creates two types of lipid columns (intra-octamer and inter-octamer). If the diameter of the octamers is ~7 nm, these columns would be ~ 3.5 nm apart.