Similarities to amyloid-β models and sequences
In noting the 11-residue repeating segments of Synucleins (segments Nt
and NAC), authors often point to the similarity to apolipoprotein
sequences. This is understandable because portions of apolipoprotein
sequences do have some 11-residue amphipathic α-helical repeating
segments and α-Syn adopts a conformation with two antiparallel α-helices
upon interactions with negatively charged membrane surfaces [16].
Furthermore, in early stages of development α-Syn can form small
oligomers that fractionally occupy helical secondary structures
[41-43]. These dynamic oligomers gradually morph into primarily β
oligomers, possibly transitioning through a 310 helical
phase [41,44]. Helical tetramers have been touted to be the primary
native form in human brains [41,44], but others claim it is
disordered monomers [45]. In general, the presence of α-helices in
α-Syn oligomers appears to dissipate with time as β secondary structure
increases.
Although the positions of charged residues that make the helices
amphipathic are conserved among the α-Syn and β-Syn families, the
following aspects indicate that much of the sequence conservation has
occurred to preserve other types of structures: 1) Nt has ten valines
and only two leucines even though leucine is more hydrophobic and has a
higher propensity for α secondary structures whereas valine has a higher
propensity for β secondary structure [36]. 2) The threonine of the
signature sequences occur on the hydrophobic face of the α-helices even
though it has a higher propensity for β-secondary structure and has a
polar hydroxyl group. 3) All signature sequences contain a glycine even
though glycine has a much higher propensity for coils and turns than for
α secondary structure. 4) Six conserved hydrophobic side chains occur on
the polar faces of the Nt α-helices.
Similarities between Synuclein and Aβ sequences generally have been
overlooked. In modeling of Aβ42 assemblies we divided the sequence into
three segments of about the same length (Fig. 3b). The second, Aβ2, and
third, Aβ3, of these segments form β-strands in numerous fibril
structures [46-48], and the first, Aβ1, has a bent β structure in
some fibrils [49,50]. In our models of Aβ42 hexamers, Aβ3 forms a
hydrophobic six-stranded antiparallel β-barrel that is surrounded by an
antiparallel β-barrel formed by Aβ1 and Aβ2 (Fig. 3a). The 3-fold radial
symmetry and 2-fold perpendicular symmetry of this Type 2 model allows
all subunits to have the same conformation and interactions. Sy2 and Sy4
sequences of α-Syn are quite similar to those of Aβ2; i.e ., they
have a 5-6 residue-long hydrophobic segment (depending upon how one
classifies glycine) flanked by charged residues (Fig. 3b). Sy1, Sy3, and
Sy5 segments have a similar sequence except for a charged residue in the
middle of the hydrophobic region. This gives them a slight resemblance
to Aβ1. Two portions of the sequence of the NAC domain have longer
hydrophobic regions that are quite similar to that of Aβ3; the three
sequences are dominated by glycine, alanine and residues with
moderate-sized side-chains that have high β propensity because they
branch at the β-carbon (threonine, valine, and isoleucine).