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The Ability of DNAJB6b to Suppress Amyloid Formation Depends on the Chaperone Aggregation State

Carlsson, Andreas LU ; Axell, Emil LU ; Emanuelsson, Cecilia LU orcid ; Olsson, Ulf LU and Linse, Sara LU (2024) In ACS Chemical Neuroscience
Abstract

For many chaperones, a propensity to self-assemble correlates with function. The highly efficient amyloid suppressing chaperone DNAJB6b has been reported to oligomerize. A key question is whether the DNAJB6b self-assemblies or their subunits are active units in the suppression of amyloid formation. Here, we address this question using a nonmodified chaperone. We use the well-established aggregation kinetics of the amyloid β 42 peptide (Aβ42) as a readout of the amyloid suppression efficiency. The experimental setup relies on the slow dissociation of DNAJB6b assemblies upon dilution. We find that the dissociation of the chaperone assemblies correlates with its ability to suppress fibril formation. Thus, the data show that the subunits of... (More)

For many chaperones, a propensity to self-assemble correlates with function. The highly efficient amyloid suppressing chaperone DNAJB6b has been reported to oligomerize. A key question is whether the DNAJB6b self-assemblies or their subunits are active units in the suppression of amyloid formation. Here, we address this question using a nonmodified chaperone. We use the well-established aggregation kinetics of the amyloid β 42 peptide (Aβ42) as a readout of the amyloid suppression efficiency. The experimental setup relies on the slow dissociation of DNAJB6b assemblies upon dilution. We find that the dissociation of the chaperone assemblies correlates with its ability to suppress fibril formation. Thus, the data show that the subunits of DNAJB6b assemblies rather than the large oligomers are the active forms in amyloid suppression. Our results provide insights into how DNAJB6b operates as a chaperone and illustrate the importance of established assembly equilibria and dissociation rates for the design of kinetic experiments.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Amyloid beta peptides, Amyloid inhibition, Chaperone activity, Oligomer dissociation, Protein aggregation, Self-assembly
in
ACS Chemical Neuroscience
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85191189404
  • pmid:38640082
ISSN
1948-7193
DOI
10.1021/acschemneuro.4c00120
language
English
LU publication?
yes
id
5e627297-f529-4d43-9d1f-6a16c181b09a
date added to LUP
2024-05-03 14:19:01
date last changed
2024-05-17 16:44:42
@article{5e627297-f529-4d43-9d1f-6a16c181b09a,
  abstract     = {{<p>For many chaperones, a propensity to self-assemble correlates with function. The highly efficient amyloid suppressing chaperone DNAJB6b has been reported to oligomerize. A key question is whether the DNAJB6b self-assemblies or their subunits are active units in the suppression of amyloid formation. Here, we address this question using a nonmodified chaperone. We use the well-established aggregation kinetics of the amyloid β 42 peptide (Aβ42) as a readout of the amyloid suppression efficiency. The experimental setup relies on the slow dissociation of DNAJB6b assemblies upon dilution. We find that the dissociation of the chaperone assemblies correlates with its ability to suppress fibril formation. Thus, the data show that the subunits of DNAJB6b assemblies rather than the large oligomers are the active forms in amyloid suppression. Our results provide insights into how DNAJB6b operates as a chaperone and illustrate the importance of established assembly equilibria and dissociation rates for the design of kinetic experiments.</p>}},
  author       = {{Carlsson, Andreas and Axell, Emil and Emanuelsson, Cecilia and Olsson, Ulf and Linse, Sara}},
  issn         = {{1948-7193}},
  keywords     = {{Amyloid beta peptides; Amyloid inhibition; Chaperone activity; Oligomer dissociation; Protein aggregation; Self-assembly}},
  language     = {{eng}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Chemical Neuroscience}},
  title        = {{The Ability of DNAJB6b to Suppress Amyloid Formation Depends on the Chaperone Aggregation State}},
  url          = {{http://dx.doi.org/10.1021/acschemneuro.4c00120}},
  doi          = {{10.1021/acschemneuro.4c00120}},
  year         = {{2024}},
}