TY - JOUR TI - Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy AU - Guerrero-Ferreira, Ricardo AU - Taylor, Nicholas MI AU - Arteni, Ana-Andreea AU - Kumari, Pratibha AU - Mona, Daniel AU - Ringler, Philippe AU - Britschgi, Markus AU - Lauer, Matthias E AU - Makky, Ali AU - Verasdonck, Joeri AU - Riek, Roland AU - Melki, Ronald AU - Meier, Beat H AU - Böckmann, Anja AU - Bousset, Luc AU - Stahlberg, Henning A2 - Scheres, Sjors HW A2 - Kuriyan, John A2 - Scheres, Sjors HW VL - 8 PY - 2019 DA - 2019/12/09 SP - e48907 C1 - eLife 2019;8:e48907 DO - 10.7554/eLife.48907 UR - https://doi.org/10.7554/eLife.48907 AB - 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. KW - Parkinson's disease KW - alpha-synuclein KW - cryo-EM KW - structural biology KW - neurodegeneration JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -