Intersheet rearrangement of polypeptides during nucleation of {beta}-sheet aggregates

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 40; pp. 14272 - 14277
• Main Authors: Petty, Sarah A, Decatur, Sean M
• Format: Journal Article
• Language: English
• Published: United States 04.10.2005
• Subjects: Amyloid - biosynthesis; Kinetics; Microscopy, Atomic Force; Peptide Fragments - chemistry; Prions - chemistry; Protein Structure, Secondary; Spectroscopy, Fourier Transform Infrared; Temperature
• ISSN: 0027-8424; 1091-6490

Many neurodegenerative diseases are characterized by the accumulation of amyloid fibers in the brain, which can occur when a protein misfolds into an extended beta-sheet conformation. The nucleation of these beta-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 beta-strands of the peptide have adopted their equilibrium antiparallel beta-sheet configuration with residue 117 in register across all strands. In this article, we present the kinetic details of the realignment of these beta-strands from their fastformed nonequilibrium structure, which has no regular register of the strands, into the more ordered beta-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 beta-strands by the introduction of a (13)C-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 beta-sheet realigns by both the repeated detachment and annealing of strands in solution and reptation of polypeptide strands within an aggregate.