Abstract

Amyloid diseases such as Alzheimer, Parkinson, and prion diseases are associated with a specific form of protein mis-folding and aggregation into oligomers and fibrils rich in beta-sheet structure. The BRICHOS domain consisting of similar to 100 residues is found in membrane proteins associated with degenerative and proliferative disease, including lung fibrosis (surfactant protein C precursor; pro-SP-C) and familial dementia (Bri2). We find that recombinant BRICHOS domains from Bri2 and pro-SP-C prevent fibril formation of amyloid beta-peptides (A beta(40) and A beta(42)) far below the stoichiometric ratio. Kinetic experiments show that a main effect of BRICHOS is to prolong the lag time in a concentration-dependent, quantitative, and reproducible manner. An ongoing aggregation process is retarded if BRICHOS is added at any time during the lag phase, but it is too late to interfere at the end of the process. Results from circular dichroism and NMR spectroscopy, as well as analytical size exclusion chromatography, imply that A beta is maintained as an unstructured monomer during the extended lag phase in the presence of BRICHOS. Electron microscopy shows that although the process is delayed, typical amyloid fibrils are eventually formed also when BRICHOS is present. Structural BRICHOS models display a conserved array of tyrosine rings on a five-stranded beta-sheet, with inter-hydroxyl distances suited for hydrogen-bonding peptides in an extended beta-conformation. Our data imply that the inhibitory mechanism is reliant on BRICHOS interfering with molecular events during the lag phase.

Published in

Journal of Biological Chemistry
2012, Volume: 287, number: 37, pages: 31608-31617
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

SLU Authors

• Willander, Hanna

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    
  • Karolinska Institute

• Presto, Jenny

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    
  • Karolinska Institute

• Askarieh, Glareh

  • Department of Molecular Biology, Swedish University of Agricultural Sciences
    

• Knight, Stefan David

  • Department of Molecular Biology, Swedish University of Agricultural Sciences
    

• Johansson, Jan

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

UKÄ Subject classification

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Biomaterials Science


Publication identifier

DOI: https://doi.org/10.1074/jbc.M112.393157

Permanent link to this page (URI)

https://res.slu.se/id/publ/43044