Octamers with solid cores.
Two Type 2P tetramers may merge to form an octamer with a similar
concentric β-barrel structure and a highly conserved apolar core (Fig.
11); the tetra and octamer models each have an 8-stranded inner
β-barrel, a 16 stranded 2nd β-barrel, and a 24-stranded third β-barrel.
The octamer model has an additional, but tentative, fourth β-barrel
formed by Ct domains. Although the relative positions of Nt strands
within and between the monomers are the same in both models, these
segments comprise the 2nd and 3rdbarrel in the octamer. A major difference is that the highly conserved
hydrophobic Sy8 strands comprise the innermost 8-stranded β-barrel in
the octamer. S/N must be 1.0 for the core barrel to have 4-fold radial
symmetry; thus, strands of all but the outer barrels are tilted by 36°
and the gap distances between barrels is ~ 0.76 nm. Of
all models presented here, these tetramer and octamer ones are most
consistent with the patterns of conservation among the three synuclein
families. The strands of the first three β-barrels all have at least six
residues that, with the exception of a few outwardly oriented residues
of the third barrel’s Sy1,3,5 segments, are apolar or have only hydroxyl
side chain moieties. Almost all β-barrel residues interior to the wall
of the 3rd barrel are small and identical in α-Syn and
β-syn. Poorly conserved Sy6, Sy7, and the Ct1 segments extend above and
below the core tri-β-barrels where they connect strands of different
β-barrels.
We developed atomic scale models of the octamer in order to explore and
illustrate the feasibility of the structure in more detail (Fig. 11
e-q). The backbone and secondary structures of the model are illustrated
by rainbow-colored ribbons (e-h). Cross-sections showing side-chains
colored by element demonstrate relatively dense side-chain packing
(i-m). Residues that are identical in α-Syn and β-Syn cluster together
to form a densly-packed core. Residues that differ in the two sequences
and where indels occur are located primarily on the surface and/or
interact with other non-conserved residues (n-q). Charged side chains of
the Nt and NAC domains can all form salt bridges.