Bri2 BRICHOS Client Specificity and Chaperone Activity Are Governed by Assembly State

Nat Commun. 2017 Dec 12;8(1):2081. doi: 10.1038/s41467-017-02056-4.

Abstract

Protein misfolding and aggregation is increasingly being recognized as a cause of disease. In Alzheimer's disease the amyloid-β peptide (Aβ) misfolds into neurotoxic oligomers and assembles into amyloid fibrils. The Bri2 protein associated with Familial British and Danish dementias contains a BRICHOS domain, which reduces Aβ fibrillization as well as neurotoxicity in vitro and in a Drosophila model, but also rescues proteins from irreversible non-fibrillar aggregation. How these different activities are mediated is not known. Here we show that Bri2 BRICHOS monomers potently prevent neuronal network toxicity of Aβ, while dimers strongly suppress Aβ fibril formation. The dimers assemble into high-molecular-weight oligomers with an apparent two-fold symmetry, which are efficient inhibitors of non-fibrillar protein aggregation. These results indicate that Bri2 BRICHOS affects qualitatively different aspects of protein misfolding and toxicity via different quaternary structures, suggesting a means to generate molecular chaperone diversity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / metabolism
  • Amyloid Neuropathies, Familial
  • Amyloid beta-Peptides / metabolism*
  • Cataract / pathology*
  • Cerebellar Ataxia / pathology*
  • Cerebral Amyloid Angiopathy, Familial / pathology*
  • Circular Dichroism
  • Deafness / pathology*
  • Dementia / pathology*
  • Humans
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / ultrastructure
  • Microscopy, Electron, Transmission
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / metabolism
  • Molecular Chaperones / ultrastructure
  • Protein Aggregation, Pathological / pathology*
  • Protein Binding
  • Protein Domains / physiology
  • Protein Folding
  • Protein Multimerization / physiology
  • Recombinant Proteins

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • ITM2B protein, human
  • Membrane Glycoproteins
  • Molecular Chaperones
  • Recombinant Proteins

Supplementary concepts

  • Dementia, familial Danish