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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2021
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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. |
format | Online Article Text |
id | pubmed-8729806 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
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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