Electrostatically-guided inhibition of Curli amyloid nucleation by the CsgC-like family of chaperones.
Polypeptide aggregation into amyloid is linked with several debilitating human diseases. Despite the inherent risk of aggregation-induced cytotoxicity, bacteria control the export of amyloid-prone subunits and assemble adhesive amyloid fibres during biofilm formation. An Escherichia protein, CsgC potently inhibits amyloid formation of curli amyloid proteins. Here we unlock its mechanism of action, and show that CsgC strongly inhibits primary nucleation via electrostatically-guided molecular encounters, which expands the conformational distribution of disordered curli subunits. This delays the formation of higher order intermediates and maintains amyloidogenic subunits in a secretion-competent form. New structural insight also reveal that CsgC is part of diverse family of bacterial amyloid inhibitors. Curli assembly is therefore not only arrested in the periplasm, but the preservation of conformational flexibility also enables efficient secretion to the cell surface. Understanding how bacteria safely handle amyloidogenic polypeptides contribute towards efforts to control aggregation in disease-causing amyloids and amyloid-based biotechnological applications.
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Jonathan D
JD
Taylor
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
William J
WJ
Hawthorne
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Joanne
J
Lo
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Alexander
A
Dear
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Neha
N
Jain
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Georg
G
Meisl
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Maria
M
Andreasen
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Catherine
C
Fletcher
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Marion
M
Koch
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Nicholas
N
Darvill
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Nicola
N
Scull
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Andrés
A
Escalera-Maurer
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Lea
L
Sefer
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Rosemary
R
Wenman
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Sebastian
S
Lambert
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Jisoo
J
Jean
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Yingqi
Y
Xu
Department of Chemical Engineering, Imperial College London, London, SW7 2AZ, UK.
Benjamin
B
Turner
Department of Chemical Engineering, Imperial College London, London, SW7 2AZ, UK.
Sergei G
SG
Kazarian
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Matthew R
MR
Chapman
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Doryen
D
Bubeck
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Alfonso
A
de Simone
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Tuomas P J
TP
Knowles
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Steve J
SJ
Matthews
D021581:Active Transport, Cell Nucleus; D000682:Amyloid / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D009994:Osmolar Concentration; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D055672:Static Electricity
D000682:Amyloid; C556817:CsgC protein, E coli; D029968:Escherichia coli Proteins; D018832:Molecular Chaperones