Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 23, Issue 5, Pages 409-415Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3194
Keywords
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Funding
- US National Institutes of Health (NIH) [R01-GM073770, P50-NS053488, P01-AG002132]
- NIH National Center for Research Resources (NCRR) [S10-RR025037]
- NIH Molecular Biophysics Training Grant at the University of Illinois at Urbana-Champaign [T32-GM008276]
- US National Science Foundation Graduate Research Fellowship
- Intramural Research Program of the Center for Information Technology at NIH
- US Department of Energy (DOE), Office of Biological and Environmental Research
- DOE [DE-FG02-07ER46453, DE-FG02-07ER46471]
- NIH NCRR [S10-RR011966]
- NIH
- [T32-AG000255]
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Misfolded alpha-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 alpha-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 beta-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 alpha-synuclein with other proteins and small molecules, to aid in PD diagnosis and treatment.
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