title: Structural comparison of mouse and human α-synuclein amyloid fibrils by solid-state NMR.
abstract: Fibrillar α-synuclein (AS) is the major component of Lewy bodies, the pathological hallmark of Parkinson's disease. Mouse AS (mAS) aggregates much faster than human AS (hAS), although mAS differs from hAS at only seven positions in its primary sequence. Currently, little is known about the site-specific structural differences between mAS and hAS fibrils. Here, we applied state-of-the-art solid-state nuclear magnetic resonance (ssNMR) methods to structurally characterize mAS fibrils. The assignment strategy employed a set of high-resolution 2D and 3D ssNMR spectra recorded on uniformly [(13)C, (15)N], [1-(13)C]glucose, and [2-(13)C]glucose labeled mAS fibrils. An almost complete resonance assignment (96% of backbone amide (15)N and 93% of all (13)C nuclei) was obtained for residues from Gly41 to Val95, which form the core of mAS fibrils. Six β-strands were identified to be within the fibril core of mAS based on a secondary chemical shift and NHHC analysis. Intermolecular (13)C:(15)N labeled restraints obtained from mixed 1:1 (13)C/(15)N-labeled mAS fibrils reveal a parallel, in-register supramolecular β-sheet arrangement. The results were compared in detail to recent structural studies on hAS fibrils and indicate the presence of a structurally conserved motif comprising residues Glu61-Lys80.
authors.affiliation: Department of NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany.
authors.forename: Guohua
authors.initials: G
authors.lastname: Lv
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.forename: Maria L
authors.initials: ML
authors.lastname: Orcellet
authors.forename: Dietmar
authors.initials: D
authors.lastname: Riedel
authors.forename: Claudio O
authors.initials: CO
authors.lastname: Fernández
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.forename: Adam
authors.initials: A
authors.lastname: Lange
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D017124:Conserved Sequence; D006801:Humans; D016631:Lewy Bodies / Q000737:chemistry; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein