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Enhanced fibril fragmentation of N-terminally truncated and Pyroglutamyl-modified Aβ peptides

: Wulff, Melanie; Baumann, Monika; Thümmler, Anka; Yadav, Jay K.; Heinrich, Liesa; Knüpfer, Uwe; Schlenzig, Dagmar; Schierhorn, Angelika; Rahfeld, Jens-Ulrich; Horn, Uwe; Balbach, Jochen; Demuth, Hans-Ulrich; Fändrich, Marcus


Angewandte Chemie. International edition 55 (2016), No.16, pp.5081-5084
ISSN: 1433-7851
ISSN: 0044-8249
ISSN: 0570-0833
ISSN: 1521-3773
Deutsche Forschungsgemeinschaft DFG
SFB 610; FA456/12-1
Journal Article
Fraunhofer IZI ()
amyloids; covalent protein modifications; Alzheimer's disease; peptide aggregation; protein folding

N-terminal truncation and pyroglutamyl (pE) formation are naturally occurring chemical modifications of the A peptide in Alzheimer's disease. We show herein that these two modifications significantly reduce the fibril length and the transition midpoint of thermal unfolding of the fibrils, but they do not substantially perturb the fibrillary peptide conformation. This observation implies that the Nterminus of the unmodified peptide protects A fibrils against mechanical stress and fragmentation and explains the high propensity of pE-modified peptides to form small and particularly toxic aggregates.