Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy
- University of Basel, Switzerland
- University of Copenhagen, Denmark
- CNRS, Université Paris Sud, Université Paris-Saclay, France
- ETH Zürich, Switzerland
- Roche Innovation Center Basel, Switzerland
- CNRS, France
- University of Lyon, France
Abstract
Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1-121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50-57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.
Data availability
Raw cryo-EM micrographs are available in EMPIAR, entry numbers EMPIAR-10323. The 3D maps are available in the EMDB, entry numbers EMD-10307 (α-Syn polymorph 2a) and EMD-10305 (α-Syn-polymorph 2b). Atomic coordinates are available at the PDB with entry numbers PDB 6SSX (α-Syn polymorph 2a) and PDB 6SST (α-Syn polymorph 2b).
Article and author information
Author details
Ricardo Guerrero-Ferreira
Nicholas MI Taylor
Ana-Andreea Arteni
Funding
Novo Nordisk (NNF14CC0001)
- Nicholas MI Taylor
SERI (17.00038)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
Fondation Bettencourt Schueller
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
fondation pour la Recherche Medicale (Contract DEQ 20160334896)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
Fondation Simone et Cino Del Duca of the Institut de France and
- Beat H Meier
- Luc Bousset
EC Joint Program on Neurodegenerative Diseases (TransPathND)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
FRISBI (ANR-10-INSB-05-01)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
EC Joint Program on Neurodegenerative Diseases (ANR-17-JPCD-0005-01)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
EC Joint Program on Neurodegenerative Diseases (ANR-17-JPCD-0002-02)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
EC Joint Program on Neurodegenerative Diseases (Protest-70)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
Synapsis Foundation (n/a)
- Ricardo Guerrero-Ferreira
- Henning Stahlberg
Heidi-Seiler Stiftung (n/a)
- Ricardo Guerrero-Ferreira
- Henning Stahlberg
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII3_154461)
- Ricardo Guerrero-Ferreira
- Nicholas MI Taylor
- Henning Stahlberg
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII5_177195)
- Ricardo Guerrero-Ferreira
- Henning Stahlberg
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (20020_178792)
- Ricardo Guerrero-Ferreira
- Henning Stahlberg
Agence Nationale de la Recherche (ANR-12-BS08-0013-01)
- Ronald Melki
- Luc Bousset
LABEX ECOFECT (ANR-11-LABX-0048)
- Anja Böckmann
H2020 (IMPRiND)
- Ana-Andreea Arteni
- Ronald Melki
- Luc Bousset
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, 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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Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy
eLife 8:e48907.
https://doi.org/10.7554/eLife.48907
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