Structural basis for reversible amyloids of hnRNPA1 elucidates their role in stress granule assembly

Nat Commun. 2019 May 1;10(1):2006. doi: 10.1038/s41467-019-09902-7.

Abstract

Subcellular membrane-less organelles consist of proteins with low complexity domains. Many of them, such as hnRNPA1, can assemble into both a polydisperse liquid phase and an ordered solid phase of amyloid fibril. The former mirrors biological granule assembly, while the latter is usually associated with neurodegenerative disease. Here, we observe a reversible amyloid formation of hnRNPA1 that synchronizes with liquid-liquid phase separation, regulates the fluidity and mobility of the liquid-like droplets, and facilitates the recruitment of hnRNPA1 into stress granules. We identify the reversible amyloid-forming cores of hnRNPA1 (named hnRACs). The atomic structures of hnRACs reveal a distinct feature of stacking Asp residues, which contributes to fibril reversibility and explains the irreversible pathological fibril formation caused by the Asp mutations identified in familial ALS. Our work characterizes the structural diversity and heterogeneity of reversible amyloid fibrils and illuminates the biological function of reversible amyloid formation in protein phase separation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / genetics
  • Amyloid / metabolism
  • Amyloid / ultrastructure*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology
  • Asparagine / genetics
  • Asparagine / metabolism
  • Cytoplasmic Granules / metabolism*
  • Cytoplasmic Granules / ultrastructure
  • HeLa Cells
  • Heterogeneous Nuclear Ribonucleoprotein A1 / genetics
  • Heterogeneous Nuclear Ribonucleoprotein A1 / isolation & purification
  • Heterogeneous Nuclear Ribonucleoprotein A1 / metabolism
  • Heterogeneous Nuclear Ribonucleoprotein A1 / ultrastructure*
  • Humans
  • Microscopy, Electron, Transmission
  • Models, Molecular
  • Mutation
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / ultrastructure
  • X-Ray Diffraction

Substances

  • Amyloid
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Recombinant Proteins
  • hnRNPA1 protein, human
  • Asparagine

Supplementary concepts

  • Amyotrophic lateral sclerosis 1