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

Elife. 2019 Dec 9;8:e48907. doi: 10.7554/eLife.48907.

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 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.

Keywords: E. coli; Parkinson's disease; alpha-synuclein; cryo-EM; human; molecular biophysics; neurodegeneration; neuroscience; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cryoelectron Microscopy / methods*
  • Cytoskeleton / chemistry*
  • Escherichia coli
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Mutation
  • Parkinson Disease
  • Protein Conformation
  • alpha-Synuclein / chemistry*

Substances

  • SNCA protein, human
  • alpha-Synuclein

Associated data

  • PDB/6SSX
  • PDB/EMD-10305
  • PDB/6SST

Grant support