NR AUDM
AU Petty,S.A.; Decatur,S.M.
TI Intersheet rearrangement of polypeptides during nucleation of ß-sheet aggregates
QU Proceedings of the National Academy of Sciences of the United States of America 2005 Oct 4; 102(40): 14272-7
IA http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1242284
PT journal article
AB 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.
MH Amyloid/*biosynthesis; Comparative Study; Kinetics; Microscopy, Atomic Force; Peptide Fragments/*chemistry; Prions/*chemistry; *Protein Structure, Secondary; Spectroscopy, Fourier Transform Infrared; Temperature
AD Department of Chemistry, Mount Holyoke College, South Hadley, MA 01075, USA
SP englisch
PO USA