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Amyloid-β oligomers are captured by the DNAJB6 chaperone : Direct detection of interactions that can prevent primary nucleation

Österlund, Nicklas ; Lundqvist, Martin LU ; Ilag, Leopold L. ; Gräslund, Astrid and Emanuelsson, Cecilia LU (2020) In The Journal of biological chemistry 295(24). p.8135-8144
Abstract

A human molecular chaperone protein, DnaJ heat shock protein family (Hsp40) member B6 (DNAJB6), efficiently inhibits amyloid aggregation. This inhibition depends on a unique motif with conserved serine and threonine (S/T) residues that have a high capacity for hydrogen bonding. Global analysis of kinetics data has previously shown that DNAJB6 especially inhibits the primary nucleation pathways. These observations indicated that DNAJB6 achieves this remarkably effective and sub-stoichiometric inhibition by interacting not with the monomeric unfolded conformations of the amyloid-β symbol (Aβ) peptide but with aggregated species. However, these pre-nucleation oligomeric aggregates are transient and difficult to study experimentally. Here,... (More)

A human molecular chaperone protein, DnaJ heat shock protein family (Hsp40) member B6 (DNAJB6), efficiently inhibits amyloid aggregation. This inhibition depends on a unique motif with conserved serine and threonine (S/T) residues that have a high capacity for hydrogen bonding. Global analysis of kinetics data has previously shown that DNAJB6 especially inhibits the primary nucleation pathways. These observations indicated that DNAJB6 achieves this remarkably effective and sub-stoichiometric inhibition by interacting not with the monomeric unfolded conformations of the amyloid-β symbol (Aβ) peptide but with aggregated species. However, these pre-nucleation oligomeric aggregates are transient and difficult to study experimentally. Here, we employed a native MS-based approach to directly detect oligomeric forms of Aβ formed in solution. We found that WT DNAJB6 considerably reduces the signals from the various forms of Aβ (1-40) oligomers, whereas a mutational DNAJB6 variant in which the S/T residues have been substituted with alanines does not. We also detected signals that appeared to represent DNAJB6 dimers and trimers to which varying amounts of Aβ are bound. These data provide direct experimental evidence that it is the oligomeric forms of Aβ that are captured by DNAJB6 in a manner which depends on the S/T residues. We conclude that, in agreement with the previously observed decrease in primary nucleation rate, strong binding of Aβ oligomers to DNAJB6 inhibits the formation of amyloid nuclei.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer disease, amyloid-beta (Aβ), chaperone DnaJ (DnaJ), native mass spectrometry, peptide, primary nucleation, protein aggregation, proteostasis
in
The Journal of biological chemistry
volume
295
issue
24
pages
10 pages
publisher
ASBMB
external identifiers
  • pmid:32350108
  • scopus:85086497493
ISSN
1083-351X
DOI
10.1074/jbc.RA120.013459
language
English
LU publication?
yes
id
e2000e21-2aae-4e35-af01-6275e5a1403a
date added to LUP
2020-07-02 13:51:47
date last changed
2020-07-03 03:00:04
@article{e2000e21-2aae-4e35-af01-6275e5a1403a,
  abstract     = {<p>A human molecular chaperone protein, DnaJ heat shock protein family (Hsp40) member B6 (DNAJB6), efficiently inhibits amyloid aggregation. This inhibition depends on a unique motif with conserved serine and threonine (S/T) residues that have a high capacity for hydrogen bonding. Global analysis of kinetics data has previously shown that DNAJB6 especially inhibits the primary nucleation pathways. These observations indicated that DNAJB6 achieves this remarkably effective and sub-stoichiometric inhibition by interacting not with the monomeric unfolded conformations of the amyloid-β symbol (Aβ) peptide but with aggregated species. However, these pre-nucleation oligomeric aggregates are transient and difficult to study experimentally. Here, we employed a native MS-based approach to directly detect oligomeric forms of Aβ formed in solution. We found that WT DNAJB6 considerably reduces the signals from the various forms of Aβ (1-40) oligomers, whereas a mutational DNAJB6 variant in which the S/T residues have been substituted with alanines does not. We also detected signals that appeared to represent DNAJB6 dimers and trimers to which varying amounts of Aβ are bound. These data provide direct experimental evidence that it is the oligomeric forms of Aβ that are captured by DNAJB6 in a manner which depends on the S/T residues. We conclude that, in agreement with the previously observed decrease in primary nucleation rate, strong binding of Aβ oligomers to DNAJB6 inhibits the formation of amyloid nuclei.</p>},
  author       = {Österlund, Nicklas and Lundqvist, Martin and Ilag, Leopold L. and Gräslund, Astrid and Emanuelsson, Cecilia},
  issn         = {1083-351X},
  language     = {eng},
  number       = {24},
  pages        = {8135--8144},
  publisher    = {ASBMB},
  series       = {The Journal of biological chemistry},
  title        = {Amyloid-β oligomers are captured by the DNAJB6 chaperone : Direct detection of interactions that can prevent primary nucleation},
  url          = {http://dx.doi.org/10.1074/jbc.RA120.013459},
  doi          = {10.1074/jbc.RA120.013459},
  volume       = {295},
  year         = {2020},
}