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

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 an...

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Autores principales: Nagaraj, Madhu, Najarzadeh, Zahra, Pansieri, Jonathan, Biverstål, Henrik, Musteikyte, Greta, Smirnovas, Vytautas, Matthews, Steve, Emanuelsson, Cecilia, Johansson, Janne, Buxbaum, Joel N., Morozova-Roche, Ludmilla, Otzen, Daniel E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729806/
https://www.ncbi.nlm.nih.gov/pubmed/35126986
http://dx.doi.org/10.1039/d1sc05790a
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author Nagaraj, Madhu
Najarzadeh, Zahra
Pansieri, Jonathan
Biverstål, Henrik
Musteikyte, Greta
Smirnovas, Vytautas
Matthews, Steve
Emanuelsson, Cecilia
Johansson, Janne
Buxbaum, Joel N.
Morozova-Roche, Ludmilla
Otzen, Daniel E.
author_facet Nagaraj, Madhu
Najarzadeh, Zahra
Pansieri, Jonathan
Biverstål, Henrik
Musteikyte, Greta
Smirnovas, Vytautas
Matthews, Steve
Emanuelsson, Cecilia
Johansson, Janne
Buxbaum, Joel N.
Morozova-Roche, Ludmilla
Otzen, Daniel E.
author_sort Nagaraj, Madhu
collection PubMed
description 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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spelling pubmed-87298062022-02-04 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 Johansson, Janne Buxbaum, Joel N. Morozova-Roche, Ludmilla Otzen, Daniel E. Chem Sci Chemistry 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. The Royal Society of Chemistry 2021-12-13 /pmc/articles/PMC8729806/ /pubmed/35126986 http://dx.doi.org/10.1039/d1sc05790a Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Nagaraj, Madhu
Najarzadeh, Zahra
Pansieri, Jonathan
Biverstål, Henrik
Musteikyte, Greta
Smirnovas, Vytautas
Matthews, Steve
Emanuelsson, Cecilia
Johansson, Janne
Buxbaum, Joel N.
Morozova-Roche, Ludmilla
Otzen, Daniel E.
Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation
title Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation
title_full Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation
title_fullStr Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation
title_full_unstemmed Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation
title_short Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation
title_sort chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729806/
https://www.ncbi.nlm.nih.gov/pubmed/35126986
http://dx.doi.org/10.1039/d1sc05790a
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