Amyloid beta-protein assembly and Alzheimer disease - PubMed (original) (raw)

Review

Amyloid beta-protein assembly and Alzheimer disease

Robin Roychaudhuri et al. J Biol Chem. 2009.

No abstract available

Figures

FIGURE 1.

A_β_ assembly. A, the sequence of A_β_42 is shown in one-letter amino acid code. The side chain charge at neutral pH is color-coded (red, negative; blue, positive). B, nucleation-dependent polymerization, reflecting the unfavorable self-association (rate constant kn+≪kn−) of X natively folded monomers (in this case, six total) to form a fibril nucleus and the favorable addition (ke+≫ke−) of a large indeterminate number of monomers to the nucleus (nascent fibril) during fibril elongation. C, A_β_self-assembly. A_β_belongs to the class of “natively disordered” proteins, existing in the monomer state as an equilibrium mixture of many conformers. On-pathway assembly requires the formation of a partially folded monomer that self-associates to form a nucleus for fibril elongation, a paranucleus (in this case, containing six monomers). Nucleation of monomer folding is a process distinct from fibril nucleation (50). Fibril nucleation is unfavorable kinetically (k2+≪k2−), which explains the lag phase of fibrillogenesis experiments, a period during which no fibril formation is apparent. Paranuclei self-associate readily (k3+≫k3−) to form protofibrils, which are relatively narrow (∼5 nm), short (<150 nm), flexible structures. These protofibrils comprise a significant but finite number (_X_) of paranuclei. Maturation of protofibrils through a process that is kinetically favorable (k4+>k4−) yields classical amyloid-type fibrils (∼10-nm diameter, indeterminate (but often >1 _μ_m) length). Other assembly pathways produce annular pore-like structures, globular dodecameric (and higher order) structures, and amylospheroids. Annuli and amylospheroids appear to be off-pathway assemblies.

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Amyloid beta-protein assembly and Alzheimer disease - PubMed (original) (raw)