Cryo-EM structure of alpha-synuclein fibrils
- University of Basel, Switzerland
- Roche Innovation Center Basel, Switzerland
- ETH Zürich, Switzerland
Abstract
Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), determined by cryo-electron microscopy structure at a resolution of 3.4Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.
Data availability
The cryo-EM image data are available in the Electron Microscopy Public Image Archive, entry number EMPIAR-10195. The 3D map is available in the EMDB, entry number EMD-4276. The atomic coordinates are available at the PDB, entry number PDB 6FLT.
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Structure of alpha-synuclein fibrilsPublicly available at the RCSB Protein Data Bank (accession no. 6FLT).
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Structure of alpha-synuclein fibrilsPublicly available at the Electron Microscopy Data Bank (accession no. EMD-4276).
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Structure of alpha-synuclein fibrilsPublicly available at the Electron Microscopy Public Image Archive (accession no. EMPIAR-10195).
Article and author information
Author details
Ricardo Guerrero-Ferreira
Nicholas M I Taylor
Funding
Swiss National Science Foundation (CRSII3_154461 and CRSII5_177195)
- Ricardo Guerrero-Ferreira
- Nicholas M I Taylor
Synapsis Foundation Switzerland
- Henning Stahlberg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Sjors HW Scheres, MRC Laboratory of Molecular Biology, United Kingdom
Version history
- Received: March 5, 2018
- Accepted: July 1, 2018
- Accepted Manuscript published: July 3, 2018 (version 1)
- Version of Record published: August 14, 2018 (version 2)
Copyright
© 2018, Guerrero-Ferreira et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cryo-EM structure of alpha-synuclein fibrils
eLife 7:e36402.
https://doi.org/10.7554/eLife.36402
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