Annular and tubular protofibrils
Amyloid oligomers typically form protofibrils which in turn morph into
fibrils. In some conditions annular protofibrils of α-Syn and mutant
A30P and A53P α-Syn form first then combine to form tubular protofibrils
[4]. We have developed Type 2P hexamer, octamer, decamer, and
dodecamer models of annular protofibrils with diameters consistent with
EM images of annular protofibrils (Fig. 12).
The general folding pattern for the A30P mutant hexamer (Fig 12 a-c)
resembles the Type 2P tetramer of Fig.10 except that Sy7 forms a
continuous β-strand that is a component of the middle barrel. There
should be few side-chain clashes between the barrels. The gap distances
between the barrels are 0.85 and 0.9 nm and the pitches of the pleats
are similar for the three β-barrels so the pleats should intermesh well.
One central inward pleat of the Ct domain has six consecutive glycines
that should fit between pleats on Sy7 and Sy8 of the middle barrel that
are composed of alanines. The central inward pleat of the middle barrel
is composed of glycines, alanines and valines and should fit between
pleats of the inner barrel.
The folding patterns for the A53T mutant octamers, decamers, and
octamers are similar; Sy6 and Sy8 each contribute an additional
β-strand/monomer to the inner and middle barrels; i.e., Sy2,4,6 comprise
the inner β-barrel, Sy1,3,5,8 comprise a middle β-barrel, and the Ct
domains that comprise an outer β-barrel of these models do not include
Sy6 (Fig. 12 e-g). The number of strands per monomer increases by one
for each concentric barrel. Sy7 is proposed to form a β-hairpin, but its
location in the illustration is somewhat arbitrary; constrained
primarily by the assumption that the folding pattern should be viable
for β-Syn that has no Sy7 segment. The gap distances between barrels
ranges from 0.6 to 0.9 nm for the four models. All three barrels of the
octamer would have S/N values of 1.0 with gap distances of
~0.76 nm between barrels. Tight packing between barrels
can be maintained by reducing S/N values of the 2ndand 3rd barrels to 0.75 and 0.60 for the decamer (Fig.
12 a-c) and dodecamer models; yielding gap distances ranging from 0.65
to 0.84 nm between barrels. Tight packing between barrels of the decamer
and dodecamer may be facilitated by intermeshing pleats because the
pitches of the three barrels are almost the same and most side-chains of
the interacting pleats are small (glycine and alanine for the central
region of the central pleat). The proposed structure of the outer Ct
barrel resembles those in Figs. 10 and 11.
The 2-fold perpendicular symmetry of Type 2 models is consistent with
the end-to-end interactions proposed for how annular protofibrils form
tubular protofibrils. Interactions among the putative Sy7 β-hairpins may
facilitate interactions among the annular protofibrils to form the
tubular protofibrils; β-Syn that lacks Sy7 does not form fibrils and the
Sy7 segment appears to be essential to fibril formation [60].