The low complexity linker of DNAJB6b is key to its anti-amyloid function
Merkelis, Timas LU ; Olsson, Ulf LU
and Linse, Sara
LU
(2025)
In QRB Discovery
6.
- Abstract
Neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, are associated with the formation of amyloid fibrils. The DNAJB6b (JB6) chaperone greatly inhibits the disease-related self-assembly of amyloid peptides in an ATP-independent manner. The molecular basis of this process is, however, not understood. Here, we studied the low complexity linker between the N- and C-terminal domains of JB6 as an isolated 110 amino acid residue construct, to get a better understanding of the role of the composition of the intact protein. We investigate the structure and aggregation behaviour of the linker and its anti-amyloid activity in comparison with the full-length chaperone. We find that the linker contains ca. 45% α-helix and 20%... (More)
Neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, are associated with the formation of amyloid fibrils. The DNAJB6b (JB6) chaperone greatly inhibits the disease-related self-assembly of amyloid peptides in an ATP-independent manner. The molecular basis of this process is, however, not understood. Here, we studied the low complexity linker between the N- and C-terminal domains of JB6 as an isolated 110 amino acid residue construct, to get a better understanding of the role of the composition of the intact protein. We investigate the structure and aggregation behaviour of the linker and its anti-amyloid activity in comparison with the full-length chaperone. We find that the linker contains ca. 45% α-helix and 20% β-sheet and is in itself an amyloid-like peptide that self-assembles into different structures, which are bigger than those formed by the intact chaperone, including fibrils. The isolated linker protects against fibril formation of Aβ42 as well as α-synuclein, but is less potent than the intact chaperone. Based on our results, we propose a possible mechanism behind JB6 and linker amyloid suppression relating to their self-assembly behaviour. In the intact protein, the domains serve to solubilize the linker such that the solution concentration of exposed linker is high enough to sustain its high potency against amyloid formation.
(Less)
- author
- Merkelis, Timas
LU
; Olsson, Ulf
LU
and Linse, Sara
LU
- organization
- publishing date
- 2025-12
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- amyloid inhibition, chaperone activity, low-complexity region, protein aggregation, protein folding
- in
- QRB Discovery
- volume
- 6
- article number
- 10016
- publisher
- Cambridge University Press
- external identifiers
-
- scopus:105023881807
- pmid:41445582
- ISSN
- 2633-2892
- DOI
- 10.1017/qrd.2025.10016
- language
- English
- LU publication?
- yes
- id
- ad1a460f-e2e9-41e0-8835-9d09c0262848
- date added to LUP
- 2026-01-12 13:37:18
- date last changed
- 2026-01-13 03:00:11
@article{ad1a460f-e2e9-41e0-8835-9d09c0262848,
abstract = {{<p>Neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, are associated with the formation of amyloid fibrils. The DNAJB6b (JB6) chaperone greatly inhibits the disease-related self-assembly of amyloid peptides in an ATP-independent manner. The molecular basis of this process is, however, not understood. Here, we studied the low complexity linker between the N- and C-terminal domains of JB6 as an isolated 110 amino acid residue construct, to get a better understanding of the role of the composition of the intact protein. We investigate the structure and aggregation behaviour of the linker and its anti-amyloid activity in comparison with the full-length chaperone. We find that the linker contains ca. 45% α-helix and 20% β-sheet and is in itself an amyloid-like peptide that self-assembles into different structures, which are bigger than those formed by the intact chaperone, including fibrils. The isolated linker protects against fibril formation of Aβ42 as well as α-synuclein, but is less potent than the intact chaperone. Based on our results, we propose a possible mechanism behind JB6 and linker amyloid suppression relating to their self-assembly behaviour. In the intact protein, the domains serve to solubilize the linker such that the solution concentration of exposed linker is high enough to sustain its high potency against amyloid formation.</p>}},
author = {{Merkelis, Timas and Olsson, Ulf and Linse, Sara}},
issn = {{2633-2892}},
keywords = {{amyloid inhibition; chaperone activity; low-complexity region; protein aggregation; protein folding}},
language = {{eng}},
publisher = {{Cambridge University Press}},
series = {{QRB Discovery}},
title = {{The low complexity linker of DNAJB6b is key to its anti-amyloid function}},
url = {{http://dx.doi.org/10.1017/qrd.2025.10016}},
doi = {{10.1017/qrd.2025.10016}},
volume = {{6}},
year = {{2025}},
}