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.
journal_name
Proc Natl Acad Sci U S Aauthors
Petty SA,Decatur SMdoi
10.1073/pnas.0502804102keywords:
subject
Has Abstractpub_date
2005-10-04 00:00:00pages
14272-7issue
40eissn
0027-8424issn
1091-6490pii
0502804102journal_volume
102pub_type
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