Equilibrium among Type 2 oligomers, protofibrils, and fibrils.
Numerous studies indicate that α-Syn oligomers and fibrils exist in a dynamic equilibrium. An overview of our working hypotheses for this equilibrium among Type 2 oligomers and fibrils is given in Fig. 17. The oligomers of Fig. 4 with diameters consistent with our tetramer models tend to aggregate in strings. Antiparallel pairs of Sy5 β-strands comprise the longest and most hydrophobic regions on the exterior Type 2A tetramers; thus, they form the most probable regions of interactions between Type 2A tetramers (green strands in top left of Fig. 17). Portions of two Sy5 strands related by 2-fold symmetry pack tightly in some fibril structures [7,8,10] and most mutations leading to early-onset PD occur in Sy5. Thus it is plausible that interactions between Sy5 segments are vital to formation of functional α-Syn assemblies and that disruptions of these interactions favor formation of toxic assemblies. In contrast, antiparallel pairs of Sy8 strands of the NAC domains form the longest and most hydrophobic regions on the exterior of Type 2P tetramers (blue strands in Fig 17). Interactions of these segments occur at regions of 2-fold symmetry in Twister type fibrils [8]. Type 2P tetramers could be favored when concentrations are sufficiently high for most tetramers to form strings or clusters that bury the NAC segments. Additional monomers may bind to tetramers to form hexamers. Likewise, tetramers and hexamers may merge to form larger assemblies such as octamers proposed for lipoproteins and octamers, decamers, and dodecamers proposed for annular protofibrils and Fe II-O2 induced oligomers. Annular protofibrils may then interact to form tubular protofibrils, which slowly morph into fibrils. But interactions are not unidirectional; under some conditions fibrils can decompose to form oligomers that become smaller with time [2].