%0 Journal Article %T Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy %V 8 %P e48907 %U https://doi.org/10.7554/eLife.48907 %X 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. %J eLife %A Guerrero-Ferreira, Ricardo %A Taylor, Nicholas MI %A Arteni, Ana-Andreea %A Kumari, Pratibha %A Mona, Daniel %A Ringler, Philippe %A Britschgi, Markus %A Lauer, Matthias E %A Makky, Ali %A Verasdonck, Joeri %A Riek, Roland %A Melki, Ronald %A Meier, Beat H %A Böckmann, Anja %A Bousset, Luc %A Stahlberg, Henning %E Scheres, Sjors HW %D December 9, 2019 %K highlight peer-reviewed