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

Marcus D. Tuttle, Gemma Comellas, Andrew J. Nieuwkoop, Dustin J. Covell, Deborah A. Berthold, Kathryn D. Kloepper, Joseph M. Courtney, Jae K. Kim, Alexander M. Barclay, Amy Kendall, William Wan, Gerald Stubbs, Charles D. Schwieters, Virginia M.Y. Lee, Julia M. George, Chad M. Rienstra

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)409-415
Number of pages7
JournalNature Structural and Molecular Biology
Volume23
Issue number5
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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