2N0A

Atomic-resolution structure of alpha-synuclein fibrils

Summary for 2N0A

• Entry DOI: 10.2210/pdb2n0a/pdb
• NMR Information: BMRB: 25518
• Descriptor: Alpha-synuclein (1 entity in total)
• Functional Keywords: protein fibril, amyloid, parkinson's disease, structural protein
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytosol : P37840
• Total number of polymer chains: 10
• Total formula weight: 144761.08

Authors

Tuttle, M.D.,Comellas, G.,Nieuwkoop, A.J.,Covell, D.J.,Berthold, D.A.,Kloepper, K.D.,Courtney, J.M.,Kim, J.K.,Schwieters, C.D.,Lee, V.M.,George, J.M.,Rienstra, C.M. (deposition date: 2015-03-04, release date: 2016-03-23, Last modification date: 2024-05-15)

Primary citation

Tuttle, M.D.,Comellas, G.,Nieuwkoop, A.J.,Covell, D.J.,Berthold, D.A.,Kloepper, K.D.,Courtney, J.M.,Kim, J.K.,Barclay, A.M.,Kendall, A.,Wan, W.,Stubbs, G.,Schwieters, C.D.,Lee, V.M.,George, J.M.,Rienstra, C.M.
Solid-state NMR structure of a pathogenic fibril of full-length human alpha-synuclein.
Nat.Struct.Mol.Biol., 23:409-415, 2016

PubMed 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.

PubMed: 27018801
DOI: 10.1038/nsmb.3194

Experimental method

SOLID-STATE NMR