Figure 3. Hexamer concentric β-barrel model. (a & b) Flattened
representation of four subunits viewed from the exterior as if the
barrel were split open on the back side and spread flat. The axes of
2-fold perpendicular symmetry are indicated by green and purple circles
behind the β-sheets, and the plane containing these axes by the
horizontal line. The arrows represent β-strands colored by segment. The
circles represent side chains; those oriented outwardly are larger than
those oriented inwardly. They are colored by residue type: white =
positively charged (blue letter), negatively charged (red letter), or
uncharged polar (black letter), green = ambivalent Gly, light gray =
ambivalent His (blue letter) or Thr (black letter), dark gray - white
letter = slightly hydrophobic Ala, black - white letter = hydrophobic.
The N- and C-termini residues have blue and red outlines to indicate
their positive and negative charges. (a) Outer β-barrel; S1a (pink), S1b
(orange), and S2 (yellow); parameters are N = 18, S/N = 1.0, D = 3.4 nm.
(b) Inner S3 β-barrel; N = 6, S/N = 1.0, D = 1.1 nm. (c) Wedge
representation cross-section on the plane containing axes of 2-fold
symmetry illustrating relative positions of the β-strands. (d-g)
Atomic-scale model. The backbone is illustrated as a rainbow-colored
ribbon from red (N-termini) to blue (C-termini). (d) View down the
radial axis of the β-barrels. (e) Side view along the 2-fold axis
between the yellow S2 strands. (f) Radial cross-section through the
central portion with side chains colored by element; hydrogens and
carbons are white and gray, polar oxygen and nitrogen atoms are red and
blue. Rectangles enclose exposed V18 and F20 side chains. (g) Ribbon
representations of six hexamers forming a beaded APF; the insert in the
upper right corner is an averaged EM image from Fig. 2.
The exterior surface of the hexamer model has three hydrophobic patches
formed by V18 and F20 (rectangles of Fig. 3f) flanked by positively
charged K18 and negatively charged E22. These are the most probable
interaction regions between APFs in an aqueous solution due to a
combination of hydrophobic and electrostatic interactions. Such
interactions should be geometrically optimal for hexamers in a bAPF
formed from six small beads due to the 2-fold symmetry of the
interaction sites (Fig. 3g). In the beaded APF micrograph analyzed here,
six-membered APFs dominated the smallest bead APFs; 13 six-membered
rings were observed whereas the average number of other small bead bAPFs
was only about two (Fig. 2).
Experimental studies indicate that Aβ42 can form
dodecamers48,49 and
octadecamers50,51, and that these sizes of oligomers
can be isolated from brains of Alzheimer’s patients. Some of these may
form when additional monomers bind to hexamers. If so, the S3 strands of
the additional Aβ monomers will likely bind in a hydrophobic
environment. Site-Directed spin-labeling studies indicate that mobility
decreases and rigidity increases within Aβ oligomers from the N-terminus
to the C-terminus, and that S3 segments are tightly
packed52. S1s comprise the most polar, most dynamic,
and least conserved of the segments; so much so that in most
experimentally-determined structures they are classified as disordered.
We hypothesize that S1 segments can be displaced as S2 and/or S3
segments of six additional monomers bind next to S3s and between S2s of
the original hexamer (Figs. 4 & 5). The displaced S1a-S1b β-hairpins of
the original hexamer may combine with S1a-S1b β-hairpins of the
additional monomers to form an outer 24-stranded antiparallel β-barrel
with approximate 6-fold radial symmetry (Fig 4), but the outermost
barrel or layer is likely to be highly dynamic and difficult to predict
precisely.