Reducing the Amyloidogenicity of Functional Amyloid Protein FapC Increases Its Ability To Inhibit α-Synuclein Fibrillation

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DOI

Functional amyloid (FA) proteins have evolved to assemble into fibrils with a characteristic cross-β structure, which stabilizes biofilms and contributes to bacterial virulence. Some of the most studied bacterial FAs are the curli protein CsgA, expressed in a wide range of bacteria, and FapC, produced mainly by members of the Pseudomonas genus. Though unrelated, both CsgA and FapC contain imperfect repeats believed to drive the formation of amyloid fibrils. While much is known about CsgA biogenesis and fibrillation, the mechanism of FapC fibrillation remains less explored. Here, we show that removing the three imperfect repeats of FapC (FapC Î"R1R2R3) slows down the fibrillation but does not prevent it. The increased lag phase seen for FapC Î"R1R2R3 allows for disulfide bond formation, which further delays fibrillation. Remarkably, these disulfide-bonded species of FapC Î"R1R2R3 also significantly delay the fibrillation of human α-synuclein, a key protein in Parkinson's disease pathology. This attenuation of α-synuclein fibrillation was not seen for the reduced form of FapC Î"R1R2R3. The results presented here shed light on the FapC fibrillation mechanism and emphasize how unrelated fibrillation systems may share such common fibril formation mechanisms, allowing inhibitors of one fibrillating protein to affect a completely different protein.

Original languageEnglish
JournalACS Omega
Volume4
Issue2
Pages (from-to)4029-4039
Number of pages11
ISSN2470-1343
DOIs
Publication statusPublished - Feb 2019

    Research areas

  • AGGREGATION, BIOFILM FORMATION, BIOGENESIS, BRAIN, CLASSIFICATION, CURLI, FILAMENTS, GASTROINTESTINAL-TRACT, INNERVATION, PARKINSONS-DISEASE

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