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Enhanced Fibril Fragmentation of N‐Terminally Truncated and Pyroglutamyl‐Modified Aβ Peptides |
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| Authors: | Melanie Wulff Monika Baumann Anka Thümmler Dr. Jay K. Yadav Liesa Heinrich Uwe Knüpfer Dagmar Schlenzig Dr. Angelika Schierhorn Dr. Jens‐Ulrich Rahfeld Dr. Uwe Horn Prof. Dr. Jochen Balbach Prof. Dr. Hans‐Ulrich Demuth Prof. Dr. Marcus Fändrich |
| Affiliation: | 1. Institute for Pharmaceutical Biotechnologie, Ulm University, Ulm, Germany;2. Institute of Physics, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany;3. Probiodrug AG, Biocenter, Halle (Saale), Germany;4. Nomad Bioscience GmbH, Biocenter, Halle (Saale), Germany;5. Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Rajasthan, India;6. Leibniz Institute for Natural Product Research and Infection Biology, Hans Kn?ll Institute, Jena, Germany;7. Department of Drug Design and Target Validation MWT Halle/Saale, Fraunhofer Institute for Cell Therapy and Immunology IZI Leipzig, Biocenter, Halle (Saale), Germany;8. Service Unit for Mass Spectrometry, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany |
| Abstract: | N‐terminal truncation and pyroglutamyl (pE) formation are naturally occurring chemical modifications of the Aβ 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 N terminus of the unmodified peptide protects Aβ fibrils against mechanical stress and fragmentation and explains the high propensity of pE‐modified peptides to form small and particularly toxic aggregates. |
| Keywords: | amyloids covalent protein modifications Alzheimer's disease peptide aggregation protein folding |