title: The bacterial curli system possesses a potent and selective inhibitor of amyloid formation.
abstract: Curli are extracellular functional amyloids that are assembled by enteric bacteria during biofilm formation and host colonization. An efficient secretion system and chaperone network ensures that the major curli fiber subunit, CsgA, does not form intracellular amyloid aggregates. We discovered that the periplasmic protein CsgC was a highly effective inhibitor of CsgA amyloid formation. In the absence of CsgC, CsgA formed toxic intracellular aggregates. In vitro, CsgC inhibited CsgA amyloid formation at substoichiometric concentrations and maintained CsgA in a non-β-sheet-rich conformation. Interestingly, CsgC inhibited amyloid assembly of human α-synuclein, but not Aβ42, in vitro. We identified a common D-Q-Φ-X0,1-G-K-N-ζ-E motif in CsgC client proteins that is not found in Aβ42. CsgC is therefore both an efficient and selective amyloid inhibitor. Dedicated functional amyloid inhibitors may be a key feature that distinguishes functional amyloids from disease-associated amyloids.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1048, USA.
authors.forename: Margery L
authors.initials: ML
authors.lastname: Evans
authors.affiliation: Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Chorell
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Taylor
authors.affiliation: Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Jörgen
authors.initials: J
authors.lastname: Åden
authors.affiliation: Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Götheson
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1048, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Marion
authors.initials: M
authors.lastname: Koch
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Lea
authors.initials: L
authors.lastname: Sefer
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Matthews
authors.affiliation: Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wittung-Stafshede
authors.affiliation: Centre for Microbial Research, Umeå University, 901 87 Umeå, Sweden; Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Almqvist
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1048, USA; Centre for Microbial Research, Umeå University, 901 87 Umeå, Sweden. Electronic address: chapmanm@umich.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Chapman
mesh_terms: D020816:Amino Acid Motifs; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001483:Base Sequence; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D066329:Protein Aggregates / Q000187:drug effects*; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C556817:CsgC protein, E coli; D029968:Escherichia coli Proteins; D066329:Protein Aggregates; D051844:alpha-Synuclein; C489688:csgA protein, E coli