title: Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein.
abstract: Misfolded α-synuclein amyloid fibrils are the principal components of Lewy bodies and neurites, hallmarks of Parkinson's disease (PD). We present a high-resolution structure of an α-synuclein fibril, in a form that induces robust pathology in primary neuronal culture, determined by solid-state NMR spectroscopy and validated by EM and X-ray fiber diffraction. Over 200 unique long-range distance restraints define a consensus structure with common amyloid features including parallel, in-register β-sheets and hydrophobic-core residues, and with substantial complexity arising from diverse structural features including an intermolecular salt bridge, a glutamine ladder, close backbone interactions involving small residues, and several steric zippers stabilizing a new orthogonal Greek-key topology. These characteristics contribute to the robust propagation of this fibril form, as supported by the structural similarity of early-onset-PD mutants. The structure provides a framework for understanding the interactions of α-synuclein with other proteins and small molecules, to aid in PD diagnosis and treatment.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Tuttle
authors.affiliation: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Gemma
authors.initials: G
authors.lastname: Comellas
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nieuwkoop
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.|Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.|Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Covell
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Berthold
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Kathryn D
authors.initials: KD
authors.lastname: Kloepper
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Courtney
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Jae K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Barclay
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA.|Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Kendall
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA.|Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: William
authors.initials: W
authors.lastname: Wan
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA.|Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Stubbs
authors.affiliation: Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Schwieters
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.|Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.|Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Biological and Experimental Psychology, School of Biological and Chemical Sciences, Queen Mary University of London, London, UK.
authors.forename: Julia M
authors.initials: JM
authors.lastname: George
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.|Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.|Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Rienstra
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D006860:Hydrogen Bonding; D016631:Lewy Bodies / Q000737:chemistry; D051379:Mice; D009474:Neurons / Q000502:physiology; D019906:Nuclear Magnetic Resonance, Biomolecular; D010300:Parkinson Disease / Q000473:pathology; D000072417:Protein Domains; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000502:physiology
chemical_list: D000682:Amyloid; C497604:SNCA protein, human; D051844:alpha-Synuclein