Kinetic studies of amyloid β-protein fibril assembly. Differential effects of α-helix stabilization
- Author(s): Fezoui, Y
- Teplow, DB
- et al.
Published Web Locationhttps://doi.org/10.1074/jbc.M204168200
Amyloid β-protein (Aβ) fibril assembly is a defining characteristic of Alzheimer's disease. Fibril formation is a complex nucleation-dependent polymerization process characterized in vitro by an initial lag phase. To a significant degree, this phase is a consequence of the energy barrier that must be overcome in order for Aβ monomers to fold and oligomerize into fibril nuclei. Here we show that low concentrations of 2,2,2-trifluoroethanol (TFE) convert predominately unstructured Aβ monomers into partially ordered, quasistable conformers. Surprisingly, this results in a temporal decrease in the lag phase for fibril formation and a significant increase in the rate of fibril elongation. The TFE effect is concentration dependent and is maximal at ∼20% (v/v). In the presence of low concentrations of TFE, fibril formation is observed in Aβ samples at nanomolar concentration, well below the critical concentration for Aβ fibril formation in the absence of TFE. As the amount of TFE is increased above 20%, helix content progressively rises to ∼80%, a change paralleled first by a decrease in elongation rate and then by a complete cessation of fibril growth. These findings are consistent with the hypothesis that a partially folded helix-containing conformer is an intermediate in Aβ fibril assembly. The requirement that Aβ partially folds in order to assemble into fibrils contrasts with the mechanism of amyloidogenesis of natively folded proteins such as transthyretin and lysozyme, in which partial unfolding is a prerequisite. Our results suggest that in vivo, factors that affect helix formation and stability will have significant effects on the kinetics of Aβ fibril formation.
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