Phosphorylation Interferes with Maturation of Amyloid-β Fibrillar Structure in the N Terminus

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-beta (A beta) peptide and investigate how phosphorylation at serine 8 affects the structure of A beta aggregates. Serine 8 is shown to be located in a region of high conformational flexibility in monomeric A beta, which upon phosphorylation undergoes changes in local conformational dynamics. Using hydrogen-deuterium exchange NMR and fluorescence quenching techniques, we demonstrate that A beta phosphorylation at serine 8 causes structural changes in the N-terminal region of A beta 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 A beta aggregates. Our data therefore support an important role of posttranslational modifications in the structural polymorphism of amyloid aggregates and their modulatory effect on neurodegeneration.