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.