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

Guerrero-Ferreira, Ricardo and Taylor, Nicholas Mi and Arteni, Ana-Andreea and Kumari, Pratibha and Mona, Daniel and Ringler, Philippe and Britschgi, Markus and Lauer, Matthias E. and Makky, Ali and Verasdonck, Joeri and Riek, Roland and Melki, Ronald and Meier, Beat H. and Böckmann, Anja and Bousset, Luc and Stahlberg, Henning. (2019) Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy. eLife, 8. e48907.

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Official URL: https://edoc.unibas.ch/73204/

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Structural Biology (Stahlberg)
UniBasel Contributors:Stahlberg, Henning
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:31 Aug 2020 13:20
Deposited On:31 Aug 2020 13:20

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