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

Madhu Nagaraj; Zahra Najarzadeh; Jonathan Pansieri; Henrik Biverstål; Greta Musteikyte; Vytautas Smirnovas; Steve Matthews; Cecilia Emanuelsson; Janne Johansson; Joel N Buxbaum; Ludmilla Morozova-Roche; Daniel E Otzen

doi:10.1039/d1sc05790a

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

Madhu Nagaraj, Zahra Najarzadeh, Jonathan Pansieri, Henrik Biverstål, Greta Musteikyte, Vytautas Smirnovas, Steve Matthews, Cecilia Emanuelsson, Janne Johansson, Joel N Buxbaum, Ludmilla Morozova-Roche, Daniel E Otzen^*

^*Corresponding author for this work

Interdisciplinary Nanoscience Center - INANO-MBG, iNANO-huset

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13 Citations (Scopus)

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 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.

Original language	English
Journal	Chemical Science
Volume	13
Issue	2
Pages (from-to)	536-553
Number of pages	18
ISSN	2041-6520
DOIs	https://doi.org/10.1039/d1sc05790a
Publication status	Published - Jan 2022

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Nagaraj, M., Najarzadeh, Z., Pansieri, J., Biverstål, H., Musteikyte, G., Smirnovas, V., Matthews, S., Emanuelsson, C., Johansson, J., Buxbaum, J. N., Morozova-Roche, L., & Otzen, D. E. (2022). Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation. Chemical Science, 13(2), 536-553. https://doi.org/10.1039/d1sc05790a

@article{4e5cd9f89c014342b900003e51d488e5,

title = "Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation",

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 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.",

author = "Madhu Nagaraj and Zahra Najarzadeh and Jonathan Pansieri and Henrik Biverst{\aa}l and Greta Musteikyte and Vytautas Smirnovas and Steve Matthews and Cecilia Emanuelsson and Janne Johansson and Buxbaum, {Joel N} and Ludmilla Morozova-Roche and Otzen, {Daniel E}",

year = "2022",

month = jan,

doi = "10.1039/d1sc05790a",

language = "English",

volume = "13",

pages = "536--553",

journal = "Chemical Science",

issn = "2041-6520",

publisher = "Royal Society of Chemistry",

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Nagaraj, M, Najarzadeh, Z, Pansieri, J, Biverstål, H, Musteikyte, G, Smirnovas, V, Matthews, S, Emanuelsson, C, Johansson, J, Buxbaum, JN, Morozova-Roche, L & Otzen, DE 2022, 'Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation', Chemical Science, vol. 13, no. 2, pp. 536-553. https://doi.org/10.1039/d1sc05790a

Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation. / Nagaraj, Madhu; Najarzadeh, Zahra; Pansieri, Jonathan et al.
In: Chemical Science, Vol. 13, No. 2, 01.2022, p. 536-553.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Chaperones mainly suppress primary nucleation during formation of functional amyloid required for bacterial biofilm formation

AU - Nagaraj, Madhu

AU - Najarzadeh, Zahra

AU - Pansieri, Jonathan

AU - Biverstål, Henrik

AU - Musteikyte, Greta

AU - Smirnovas, Vytautas

AU - Matthews, Steve

AU - Emanuelsson, Cecilia

AU - Johansson, Janne

AU - Buxbaum, Joel N

AU - Morozova-Roche, Ludmilla

AU - Otzen, Daniel E

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85122961362&partnerID=8YFLogxK

U2 - 10.1039/d1sc05790a

DO - 10.1039/d1sc05790a

M3 - Journal article

C2 - 35126986

SN - 2041-6520

VL - 13

SP - 536

EP - 553

JO - Chemical Science

JF - Chemical Science

IS - 2

ER -

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

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