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.
(Less)
- author
- Österlund, Nicklas
; Lundqvist, Martin
LU
; Ilag, Leopold L.
; Gräslund, Astrid
and Emanuelsson, Cecilia
LU
- organization
- publishing date
- 2020
- 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
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- scopus:85086497493
- pmid:32350108
- 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
- 2024-05-29 15:36:04
@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}},
keywords = {{Alzheimer disease; amyloid-beta (Aβ); chaperone DnaJ (DnaJ); native mass spectrometry; peptide; primary nucleation; protein aggregation; proteostasis}},
language = {{eng}},
number = {{24}},
pages = {{8135--8144}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
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}},
}