title: Intersheet rearrangement of polypeptides during nucleation of {beta}-sheet aggregates.
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 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.
authors.affiliation: Department of Chemistry, Mount Holyoke College, South Hadley, MA 01075, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Petty
authors.forename: Sean M
authors.initials: SM
authors.lastname: Decatur
mesh_terms: D000682:Amyloid / Q000096:biosynthesis*; D007700:Kinetics; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D013696:Temperature
chemical_list: D000682:Amyloid; D010446:Peptide Fragments; D011328:Prions