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Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation

Nagaraj, Madhu ; Najarzadeh, Zahra ; Pansieri, Jonathan ; Biverstål, Henrik ; Musteikyte, Greta ; Smirnovas, Vytautas ; Matthews, Steve ; Emanuelsson, Cecilia LU orcid ; Johansson, Janne and Buxbaum, Joel N. , et al. (2022) In Chemical Science 13(2). p.536-553
Abstract

Unlike misfolding in neurodegenerative diseases, aggregation of functional amyloids involved in bacterial biofilm, e.g. CsgA (E. coli) and FapC (Pseudomonas), is carefully regulated. However, it is unclear whether functional aggregation is inhibited by chaperones targeting pathological misfolding and if so by what mechanism. Here we analyze how four entirely different human chaperones or protein modulators (transthyretin, S100A9, Bri2 BRICHOS and DNAJB6) and bacterial CsgC affect CsgA and FapC fibrillation. CsgA is more susceptible to inhibition than FapC and the chaperones vary considerably in the efficiency of their inhibition. However, mechanistic analysis reveals that all predominantly target primary nucleation rather than... (More)

Unlike misfolding in neurodegenerative diseases, aggregation of functional amyloids involved in bacterial biofilm, e.g. CsgA (E. coli) and FapC (Pseudomonas), is carefully regulated. However, it is unclear whether functional aggregation is inhibited by chaperones targeting pathological misfolding and if so by what mechanism. Here we analyze how four entirely different human chaperones or protein modulators (transthyretin, S100A9, Bri2 BRICHOS and DNAJB6) and bacterial CsgC affect CsgA and FapC fibrillation. CsgA is more susceptible to inhibition than FapC and the chaperones vary considerably in the efficiency of their inhibition. However, mechanistic analysis reveals that all predominantly target primary nucleation rather than elongation or secondary nucleation, while stoichiometric considerations suggest that DNAJB6 and CsgC target nuclei rather than monomers. Inhibition efficiency broadly scales with the chaperones' affinity for monomeric CsgA and FapC. The chaperones tend to target the most aggregation-prone regions of CsgA, but do not display such tendencies towards the more complex FapC sequence. Importantly, the most efficient inhibitors (Bri2 BRICHOS and DNAJB6) significantly reduce bacterial biofilm formation. This commonality of chaperone action may reflect the simplicity of functional amyloid formation, driven largely by primary nucleation, as well as the ability of non-bacterial chaperones to deploy their proteostatic capacities across biological kingdoms.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Chemical Science
volume
13
issue
2
pages
18 pages
publisher
Royal Society of Chemistry
external identifiers
  • pmid:35126986
  • scopus:85122961362
ISSN
2041-6520
DOI
10.1039/d1sc05790a
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Royal Society of Chemistry.
id
41633978-a73f-4c38-918c-8774c233e88b
date added to LUP
2022-02-11 15:50:25
date last changed
2024-05-22 01:11:59
@article{41633978-a73f-4c38-918c-8774c233e88b,
  abstract     = {{<p>Unlike misfolding in neurodegenerative diseases, aggregation of functional amyloids involved in bacterial biofilm, e.g. CsgA (E. coli) and FapC (Pseudomonas), is carefully regulated. However, it is unclear whether functional aggregation is inhibited by chaperones targeting pathological misfolding and if so by what mechanism. Here we analyze how four entirely different human chaperones or protein modulators (transthyretin, S100A9, Bri2 BRICHOS and DNAJB6) and bacterial CsgC affect CsgA and FapC fibrillation. CsgA is more susceptible to inhibition than FapC and the chaperones vary considerably in the efficiency of their inhibition. However, mechanistic analysis reveals that all predominantly target primary nucleation rather than elongation or secondary nucleation, while stoichiometric considerations suggest that DNAJB6 and CsgC target nuclei rather than monomers. Inhibition efficiency broadly scales with the chaperones' affinity for monomeric CsgA and FapC. The chaperones tend to target the most aggregation-prone regions of CsgA, but do not display such tendencies towards the more complex FapC sequence. Importantly, the most efficient inhibitors (Bri2 BRICHOS and DNAJB6) significantly reduce bacterial biofilm formation. This commonality of chaperone action may reflect the simplicity of functional amyloid formation, driven largely by primary nucleation, as well as the ability of non-bacterial chaperones to deploy their proteostatic capacities across biological kingdoms.</p>}},
  author       = {{Nagaraj, Madhu and Najarzadeh, Zahra and Pansieri, Jonathan and Biverstål, Henrik and Musteikyte, Greta and Smirnovas, Vytautas and Matthews, Steve and Emanuelsson, Cecilia and Johansson, Janne and Buxbaum, Joel N. and Morozova-Roche, Ludmilla and Otzen, Daniel E.}},
  issn         = {{2041-6520}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{2}},
  pages        = {{536--553}},
  publisher    = {{Royal Society of Chemistry}},
  series       = {{Chemical Science}},
  title        = {{Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation}},
  url          = {{http://dx.doi.org/10.1039/d1sc05790a}},
  doi          = {{10.1039/d1sc05790a}},
  volume       = {{13}},
  year         = {{2022}},
}