Tetramers
With time α-Syn oligomers tend to transition from antiparallel to parallel β-structure [3]. The β-barrels of Type 2P models are parallel within the subunits and antiparallel between the subunits. The core of the 2P tetramer model is an 8-stranded β-barrel formed by Sy2 and Sy4 (Fig. 10). It is surrounded by a 16-stranded β-barrel formed by Sy1,3,5, & 7b-8. This barrel may be surrounded by a 3rd 24-stranded antiparallel β-barrel formed by Sy6-7a and five Ct strands; however, if present this highly tentative outer barrel may be unstable and/or relatively disordered.
This model was developed to maximize interactions among and burial of apolar residues that are identical in α- and β-Syn sequences and to maximize the amount of parallel β-structure. (Reversing positions of Sy6 and Sy8 would simplify the 2P model; however, doing so would reduce clustering of the conserved apolar residues and the amount of parallel β-structure.) No residue differences occur in the putative β-strands of Sy2 and Sy4 or in all but one (A27T) inwardly-oriented side-chains of Sy1, Sy3, Sy5, or Sy8 β-strands that interact with those of Sy2 or Sy4, consistent with the hypothesis that this motif is conserved in both families. The second β-barrel of this model has four fewer β-strands and its diameter is ~0.4 nm less for the 2A tetramer model of Fig. 7, making the side-chain packing more compact in the 2P model and the distance between the walls of the two β-barrels only 0.7 nm. This tight packing is feasible because small apolar side-chains dominate the area between the inner and outer β-barrels; each monomer has seven glycines, seven alanines, six valines, two serines, one methionine, and one tyrosine side-chain between the barrels. If Type 2P tetramers are essential for the formation of some functional α- and β-Syn assemblies, then tight and precise packing of the hydrophobic core may explain why even conservative substitutions do not occur between the two families for these interacting residues.
The only charged side-chains of the putative Nt β-strands face outwardly on the middle β-barrel: the negatively charged E20 of Sy3 is positioned between positively charged K6 of Sy1 and H50 of Sy5. This outwardly oriented pleat of charged side-chains is flanked on each side by a pleat of hydrophobic side-chains.
The tentative model of the outer barrel was chosen for several reasons: (1) The inwardly oriented central pleat of adjacent subunits has eight adjacent glycines flanked by an alanine and two tyrosines on each side. The small residues of the central region should reduce side-chain clashes between the barrels. (2) The pitches of the pleats are about the same for the middle (4.8 nm) and outer barrels (4.2 nm). (3) Most prolines are located in the second position of β-turns, a frequently-observed location for prolines. (4) Indels in the α-Syn and β-Syn sequences occur in turn regions between the β-strands where they should have minimal effect on the structures. (5) Four consecutive residues (GGAV) within the Sy6 strand interact with their counterparts on an axis of 2-fold symmetry and conserved apolar residues of two interacting S8 segments of the middle β-barrel. (6) Seven of the last eight residues of the Ct domain are identical in α-Syn and β-Syn sequences and self-associate at the other 2-fold axis and cover conserved portions of two interacting Sy1 strands. (7) The rest of Sy6 and most of the Ct domain are poorly conserved and interact with less conserved portions of the middle barrel (e.g., H50Q) or the aqueous solvent. (8) The putative outer layer strands are positioned to allow connections of Sy5 to Sy6, Sy6 to Sy7, and Sy8 to Ct1. (9) The Sy7 β-hairpins are on the top and bottom of the assembly where they are exposed to solvent and should have little effect on the rest of the structure.
The model of Fig.10 f and g for the β-Syn tetramer differs somewhat; e.g., the Sy7 segment is deleted and there are some insertions in the first portion of the Ct domain. These indels should not affect the rest of the structure dramatically because they do not occur within the putative β-barrels. The outer barrels of both models have the same number of strands and a central inwardly oriented pleat (black background) composed of apolar and relatively conserved residues sould fit between outwardly oriented pleats of the middle barrel.