title: Phosphorylation Interferes with Maturation of Amyloid-β Fibrillar Structure in the N Terminus.
abstract: Neurodegeneration is characterized by the ubiquitous presence of modifications in protein deposits. Despite their potential significance in the initiation and progression of neurodegenerative diseases, the effects of posttranslational modifications on the molecular properties of protein aggregates are largely unknown. Here, we study the Alzheimer disease-related amyloid-β (Aβ) peptide and investigate how phosphorylation at serine 8 affects the structure of Aβ aggregates. Serine 8 is shown to be located in a region of high conformational flexibility in monomeric Aβ, which upon phosphorylation undergoes changes in local conformational dynamics. Using hydrogen-deuterium exchange NMR and fluorescence quenching techniques, we demonstrate that Aβ phosphorylation at serine 8 causes structural changes in the N-terminal region of Aβ aggregates in favor of less compact conformations. Structural changes induced by serine 8 phosphorylation can provide a mechanistic link between phosphorylation and other biological events that involve the N-terminal region of Aβ aggregates. Our data therefore support an important role of posttranslational modifications in the structural polymorphism of amyloid aggregates and their modulatory effect on neurodegeneration.
authors.affiliation: From the German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Strasse 3a, 37075 Göttingen, Germany, Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany, nare@nmr.mpibpc.mpg.de.
authors.forename: Nasrollah
authors.initials: N
authors.lastname: Rezaei-Ghaleh
authors.affiliation: Department of Neurology, University of Bonn, 53127 Bonn, Germany, and.
authors.forename: Sathish
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Neurology, University of Bonn, 53127 Bonn, Germany, and.
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.affiliation: From the German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Strasse 3a, 37075 Göttingen, Germany, Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany, Department of Neurology, University Medical Center, University of Göttingen, Göttingen, Waldweg 33, 37073 Göttingen, Germany markus.zweckstetter@dzne.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D041961:Deuterium Exchange Measurement; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological; D012694:Serine / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D012694:Serine
keywords: Alzheimer disease; amyloid-β (Aβ); hydrogen-deuterium exchange; nuclear magnetic resonance (NMR); phosphorylation