1. Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein
- Author
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Amy Kendall, Joseph M. Courtney, Marcus D. Tuttle, Gemma Comellas, Jae K Kim, Charles D. Schwieters, Kathryn D. Kloepper, William Wan, Chad M. Rienstra, Gerald Stubbs, Alexander M. Barclay, Virginia M.-Y. Lee, Jimin George, Andrew J. Nieuwkoop, Dustin J. Covell, and Deborah A. Berthold
- Subjects
0301 basic medicine ,Amyloid ,Protein Folding ,Stereochemistry ,Protein domain ,Fibril ,Protein Structure, Secondary ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Protein structure ,Protein Domains ,Structural Biology ,Animals ,Humans ,Amino Acid Sequence ,Protein Structure, Quaternary ,Molecular Biology ,Nuclear Magnetic Resonance, Biomolecular ,Cells, Cultured ,Alpha-synuclein ,Neurons ,Chemistry ,Hydrogen Bonding ,Parkinson Disease ,Salt bridge (protein and supramolecular) ,030104 developmental biology ,alpha-Synuclein ,Protein folding ,Lewy Bodies ,Fiber diffraction - 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.
- Published
- 2015