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Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Guerrero-Ferreira Ricardo, Taylor Nicholas MI, Arteni Ana-Andreea, Kumari Pratibha, Mona Daniel, Ringler Philippe, Britschgi Markus, Lauer Matthias E, Makky Ali, Verasdonck Joeri, Riek Roland, Melki Ronald, Meier Beat H, Böckmann Anja, Bousset Luc, Stahlberg Henning,
Project Molecular and Cellular Modulation in Parkinson's Disease
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Original article (peer-reviewed)

Journal eLife
Volume (Issue) 8
Page(s) e48907
Title of proceedings eLife
DOI 10.7554/elife.48907

Open Access

Type of Open Access Publisher (Gold Open Access)


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.