Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions
Fig 24
A model for nucleated polymerization of Alzheimer’s Aβ proteins.
(A) Domain swapping: Paranuclei and fibrils comprising parallel β-sheets. (a) The mechanism of conversion of the Aβ collapsed coils into out-of-register antiparallel dimers via split intein-like mechanism of molecular recognition, (1) at the Aβ concentration greater than the critical micelle concentration c > c*, and (2) at the Aβ concentration c < c*, in the presence of submicellar concentrations of SDS; (b) The staggered antiparallel Aβ dimer as the left-handed coiled-coil that has in addition left-handed superhelical twist, and the Aβ tetramer obtained via antiparallel association of the ‘free’ N-terminal segments (domain swapping); (c) Further aggregation via domain swapping yields a disk-shaped hexamer—paranucleus [204,264–268]. The circular complex places two dimers on top of each other. The characteristic trapezoid appearance of paranuclei in high-resolution AFM images [266], see the insert, appears to be consistent with the wedge-like shape. The strands stacked on top of each other are parallel; (d) The circular hexamer complex may also be stabilized by the edge-to-edge H-bonding within a ‘jelly-roll’-like structure which may convert into a 6-stranded antiparallel β barrel; (e) The limiting modes of stacking of the paranuclei which yield either tubular (Aβ amyloid pore [271]) or annular aggregates (Aβ nanoglobules [272]). The high-resolution AFM image of the initial stages of aggregation of the paranuclei shows stacking of disk-shaped hexamers and formation of a ring structure (red arrow). Catalysis of fibrillization by the intercalating cations and anions e.g. methylene blue, calmidazolium chloride, orcein-related O4 [276–278] suggests that conformational conversion of the antiparallel sheets β↑β’↓ and β”↑β”‘↓ of the paranuclei into parallel cross-β structure occurs in such stacks; (f) Morphological diversity of polymerization on mica support [42] appears to reflect two modes of paranuclei aggregation, and so does the structure of protofibril ‘on-path’ intermediates of fibrillization in solution [279–282]; (g) The cryoEM-derived structures of Aβ fibrils shows the expected assembly of two protofilaments comprising parallel cross-β sheets and aligned in the antiparallel fashion [283,284]; (h) Mechanism of fibril-surface catalysis of secondary nucleation [43,285,286]: formation of the Aβ dimers is facilitated by the binding of Aβ monomers along the fibril edges via antiparallel interlocking of the N-terminal segments; (i) The trimeric fibril which may be formed by remodeling of the fibril shown in panel (g) [288]. (B) Edge-to-edge assembly: Off-pathway oligomers, self-replicating non-fibrillar aggregates and fibrils comprising antiparallel β-sheets. (a) The Aβ trimer obtained by the edge-to-edge assembly. In contrast to the dimer, the trimer cannot fold into a coiled coil [154]; (b) Morphology of polymerization of Aβ on graphite [41] is consistent with the model of edge-to-edge assembly and FP-directed molecular recognition, see the text. The edge-to-edge Aβ tetramer cannot fold into a coiled coil either [154] but its polymerization via domain swapping may produce high-order oligomers that retain the staggered antiparallel alignment of strands [261,289–291]. By a combination of twist, bend and rise, such oligomers can fold into ‘jelly-roll’-like cylindrical structures; (c) Reversal of domain swapping and fragmentation within the ‘jelly-roll’-like folds of higher-order oligomers can yield fibrils comprising antiparallel cross-β structure [292,293]; (d) The alternative conversion of the ‘jelly-roll’-like cylinder involves reversal of domain swapping and the edge-to-edge closing of a β barrel. The homotrimer of tetramers can form in this way the 12-stranded antiparallel barrel which we believe represents the structure of the neuropathological Aβ globulomer [258,294] also isolated as the brain Aβ*56 oligomer [262,295,296]; (e) The 12-stranded antiparallel barrel can ‘capture’ Aβ dimers and tetramers via antiparallel interlocking of the ‘free’ N-terminal segments. This is likely the mechanism of self-replication of the off-pathway Aβ oligomers as shown in the diagram [260,297–299]. Note that the low-permittivity environment of the interior of a larger aggregate may promote strand→helix conversion in reversal of the initial stages of dimerization of Aβ [301]; (f) The alternative edge-to-edge aggregation of Aβ, the staggered (out-of-register) parallel assembly; (g) The 12-stranded antiparallel barrel may also ‘capture’ Aβ monomers that form a staggered parallel assembly and fold into 6-stranded out-of-register parallel barrel. This type of aggregation would account for the formation of the off-pathway Aβ oligomers 150±30 kDa [201,202] and the NU4-reactive Aβ oligomer ~80 kDa [300] (30-mer and 18-mer, respectively), and for the solid state NMR evidence of both antiparallel and parallel intermolecular contacts in the 150±30 kDa oligomers [201,202].