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

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

Related Articles Solid-state NMR structure of a pathogenic fibril of full-length human ?-synuclein.

Nat Struct Mol Biol. 2016 Mar 28;

Authors: Tuttle MD, Comellas G, Nieuwkoop AJ, Covell DJ, Berthold DA, Kloepper KD, Courtney JM, Kim JK, Barclay AM, Kendall A, Wan W, Stubbs G, Schwieters CD, Lee VM, George JM, Rienstra CM

Abstract
Misfolded ?-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 ?-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 ?-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 ?-synuclein with other proteins and small molecules, to aid in PD diagnosis and treatment.


PMID: 27018801 [PubMed - as supplied by publisher]



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