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

Abstract : 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 $\mathring{A}$ and 3.4 $\mathring{A}$ 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.
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Contributor : Mehdi Kabani <>
Submitted on : Tuesday, December 10, 2019 - 2:19:34 PM
Last modification on : Wednesday, September 16, 2020 - 5:48:32 PM
Long-term archiving on: : Wednesday, March 11, 2020 - 6:49:35 PM

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Ricardo Guerrero-Ferreira, Nicholas Taylor, Ana-Andreea Arteni, Pratibha Kumari, Daniel Mona, et al.. Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy. eLife, eLife Sciences Publication, 2019, 8, pp.e48907. ⟨10.7554/eLife.48907⟩. ⟨cea-02402414⟩

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