Atomic structures of FUS LC domain segments reveal bases for reversible amyloid fibril formation

Nat Struct Mol Biol. 2018 Apr;25(4):341-346. doi: 10.1038/s41594-018-0050-8. Epub 2018 Apr 2.

Abstract

Thermostable cross-β structures are characteristic of pathological amyloid fibrils, but these structures cannot explain the reversible nature of fibrils formed by RNA-binding proteins such as fused in sarcoma (FUS), involved in RNA granule assembly. Here, we find that two tandem (S/G)Y(S/G) motifs of the human FUS low-complexity domain (FUS LC) form reversible fibrils in a temperature- and phosphorylation-dependent manner. We named these motifs reversible amyloid cores, or RAC1 and RAC2, and determined their atomic structures in fibrillar forms, using microelectron and X-ray diffraction techniques. The RAC1 structure features an ordered-coil fibril spine rather than the extended β-strand typical of amyloids. Ser42, a phosphorylation site of FUS, is critical in the maintenance of the ordered-coil structure, which explains how phosphorylation controls fibril formation. The RAC2 structure shows a labile fibril spine with a wet interface. These structures illuminate the mechanism of reversible fibril formation and dynamic assembly of RNA granules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amyloid / chemistry*
  • Amyloidogenic Proteins / chemistry
  • Electrons
  • Humans
  • Models, Molecular
  • Mutation
  • Peptides / chemistry
  • Phosphorylation
  • Protein Domains
  • Protein Structure, Secondary
  • RNA / chemistry
  • RNA-Binding Protein FUS / chemistry*
  • RNA-Binding Proteins / chemistry
  • Serine / chemistry
  • Temperature
  • X-Ray Diffraction

Substances

  • Amyloid
  • Amyloidogenic Proteins
  • FUS protein, human
  • Peptides
  • RNA-Binding Protein FUS
  • RNA-Binding Proteins
  • Serine
  • RNA