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

• DOI: 10.7554/elife.48907
• Publication Date: 2019-12-09T13:00:24Z
• Authors: Ricardo Guerrero-...; Nicholas MI Taylor; Ana-Andreea Arteni; Pratibha Kumari; Daniel Mona; Philippe Ringler; Markus Britschgi; Matthias E Lauer; Ali Makky; Joeri Verasdonck; Roland Riek; Ronald Melki; Beat H Meier; Anja Böckmann; Luc Bousset; Henning Stahlberg
• Keywords: Models, Molecular; QH301-705.5; Protein Conformation; [SDV]Life Sciences [q-bio]; Parkinson's disease; alpha-synuclein; Science; 03 medical and health sciences; Escherichia coli; structural biology; Humans; [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology; Amino Acid Sequence; Biology (General); Cytoskeleton; 0303 health sciences; [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]; Q; Cryoelectron Microscopy; neurodegeneration; R; Parkinson Disease; [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]; Mutation; alpha-Synuclein; cryo-EM; Medicine; Hydrophobic and Hydrophilic Interactions; Neuroscience

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.