Figure
4. Dodecamer models. Parameters of the barrel are listed below the
octadecamer schematics. The color code for the dodecamer strands and
residues is the same as in the previous figures. The structures of the
core S2 and S3 strands of the hexamer are maintained as additional
subunits (stippled), and the core S1a-S1b hairpins (sides of outer
barrel) are displaced outwardly to the third barrel. (a) Wedge
representations of the central cross-section; peripheral subunits are
stippled. (b-d) Flattened schematics of four subunits of (b) the inner
6-stranded S3 β-barrel (same as hexamer), (c) the middle 18-stranded S2
and S3 β-barrel, and (d) the outer 24-stranded S1a-S1b β-barrel. (e-h)
Atomic-scale models of the dodecamer. (e & f) Rainbow colored ribbon
illustration of the backbone as viewed from the top and side. (g & h)
Cross-sections with side chains colored by element viewed along the
barrels’ axis and from the side. Note that most buried side chains are
tightly packed and hydrophobic (gray carbons, white hydrogens, and
yellow sulfurs), and that most surface side chains have polar red oxygen
or blue nitrogen atoms with white hydrogens.
Aβ homologs comprise a large superfamily present in most vertebrates.
Multiple studies indicate that they have a functional
role38,53,54 including antimicrobial
activity55. We aligned 2500 homologous sequences from
mammals through bony fish (Supplement Fig. S2). Residues 28 – 42 of the
S3 segment are incredibly conserved; the sequences are identical in all
but three positions and even those substitutions are limited to large
alkyl side chains: i.e., I32-V or L, V39-I, and V40-I (Fig. S2). Only
one substitution occurs at V12 in S1b, and at K16, L17, V18, F19, and
N27 in S2. Only three or four residue types occur at D1 and E3 in S1a,
at Y10 in S1b, and at Q15, F20, A21, D23, and S26 of S2. All
hypervariable positions where five or more residue types and deletions
occur are in S1 or toward the end of S2. The high degree of conservation
in S2 and S3 suggest that these proteins adopt a functional conformation
or conformations in which at least some S3 segments and conserved
portions of S2 are buried within the protein complex, and in which most
of S1a is peripheral and likely disordered. Mutagenesis studies indicate
that S3 residues I31, I32, L34, V39, V40 and I42 are key to Aβ
oligomerization56. The octadecamer model of Fig. 5 was
developed in part based on the hypothesis that all highly conserved
hydrophobic residues form a core structure that is buried in this model.
S1a is peripheral as are outwardly oriented side chains of S1b. Side
chain packing between barrels is quite tight with few large cavities;
all conserved hydrophobic side chains (blue and cyan) and most
semi-conserved side chains (yellow and green) are buried, the
hypervariable side chain positions (red) are peripheral, backbone
H-bonding is extensive, and almost all charged groups form salt bridges.