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

ABSTRACT:

SUBMITTER: Henning Stahlberg

PROVIDER: EMPIAR-10323 | biostudies-other |

REPOSITORIES: biostudies-other

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

Guerrero-Ferreira Ricardo R Taylor Nicholas Mi NM Arteni Ana-Andreea AA Kumari Pratibha P Mona Daniel D Ringler Philippe P Britschgi Markus M Lauer Matthias E ME Makky Ali A Verasdonck Joeri J Riek Roland R Melki Ronald R Meier Beat H BH Böckmann Anja A Bousset Luc L Stahlberg Henning H

eLife 20191209

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 resolu ...[more]

PMID: 31815671

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

Project description: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.

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