Solid-state NMR structure of a pathogenic fibril of full-length human alpha-synuclein
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Volume
23
Pagination
409 - 415
Publisher
DOI
10.1038/nsmb.3194
Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Issue
ISSN
1545-9993
Metadata
Show full item recordAbstract
Misfolded a-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 a-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 longrange distance restraints define a consensus structure with common amyloid features including parallel, in-register b-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 asynuclein with other proteins and small molecules, to aid in PD diagnosis and treatment.
Authors
Tuttle, MD; Comellas, G; Nieuwkoop, AJ; Covell, DJ; Berthold, DA; Kloepper, KD; Courtney, JM; Kim, JK; Barclay, AM; Kendall, ACollections
- Biology [93]