Intersheet rearrangement of polypeptides during nucleation of β-sheet aggregates

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Abstract
Many neurodegenerative diseases are characterized by the accumulation of amyloid fibers in the brain, which can occur when a protein misfolds into an extended β-sheet conformation. The nucleation of these β-sheet aggregates is of particular interest, not only because it is the rate-determining step toward fiber formation but also because early, soluble aggregate species may be the cytotoxic entities in many diseases. In the case of the prion peptide H1 (residues 109–122 of the prion protein) stable amyloid fibers form only after the β-strands of the peptide have adopted their equilibrium antiparallel β-sheet configuration with residue 117 in register across all strands. In this article, we present the kinetic details of the realignment of these β-strands from their fastformed nonequilibrium structure, which has no regular register of the strands, into the more ordered β-sheets capable of aggregating into stable fibers. This process is likely the nucleating step toward the formation of stable fibers. Isotope-edited IR spectroscopy is used to monitor the alignment of the β-strands by the introduction of a13C-labeled carbonyl at residue 117. Nonexponential kinetics is observed, with a complex dependence on concentration. The results are consistent with a mechanism in which the β-sheet realigns by both the repeated detachment and annealing of strands in solution and reptation of polypeptide strands within an aggregate.

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