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).