title: Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.
abstract: Parkinson's disease (PD) is pathologically characterized by the presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS), a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT) protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors.forename: Luisel R
authors.initials: LR
authors.lastname: Lemkau
authors.forename: Gemma
authors.initials: G
authors.lastname: Comellas
authors.forename: Shin W
authors.initials: SW
authors.lastname: Lee
authors.forename: Lars K
authors.initials: LK
authors.lastname: Rikardsen
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Woods
authors.forename: Julia M
authors.initials: JM
authors.lastname: George
authors.forename: Chad M
authors.initials: CM
authors.lastname: Rienstra
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D016631:Lewy Bodies / Q000737:chemistry; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure
chemical_list: D050505:Mutant Proteins; D051844:alpha-Synuclein