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.
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).
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© 2019, Guerrero-Ferreira et al.
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