Solid-State NMR Structure of a Pathogenic Fibril of Full-Length Human α-Synuclein

By Marcus D. Tuttle, Gemma Comellas, Andrew J. Nieuwkoop, D. Covell, D. A. Berthold, K. D. Kloepper, Joseph M. Courtney, J. K. Kim, A. M. Barclay, A. Kendall and 6 more. Nature Structural &Molecular Biology, 2016

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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.

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Citations in the corpus

Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. (2017, unknown): “…ns it y Residue number d Daebel et al. 2012 ssNMR –3.0 –1.0 –2.0 0.0 1.0 2.0 3.0 0 40 60 80 100 120 140 16020 A gg re ga ti on p ro pe ns it y Residue number b Tuttle et al. 2016 ssNMR Gath et al. 2014 ssNMR/fibrils Gath et al. 2014 ssNMR/ribbons Comellas et al. 2011 ssNMR Vilar et al. 2008 H/D…”
Structures of α-Synuclein Filaments from Multiple System Atrophy (2020, background): “20 phosphate, or of chaotropic, negatively charged ions, such as bromine (60-63).”