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Nat Struct Mol Biol. 2016 May;23(5):409-15. doi: 10.1038/nsmb.3194. Epub 2016 Mar 28.

Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein.

Author information

1
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
2
Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
3
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
4
Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
5
Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
6
Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA.
7
Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.
8
Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, Maryland, USA.
9
Department of Biological and Experimental Psychology, School of Biological and Chemical Sciences, Queen Mary University of London, London, UK.
10
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.

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.

PMID:
27018801
PMCID:
PMC5034296
DOI:
10.1038/nsmb.3194
[Indexed for MEDLINE]
Free PMC Article

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