title: Microcin amyloid fibrils A are reservoir of toxic oligomeric species.
abstract: Microcin E492 (Mcc), a low molecular weight bacteriocin produced by Klebsiella pneumoniae RYC492, has been shown to exist in two forms: soluble forms that are believed to be toxic to the bacterial cell by forming pores and non-toxic fibrillar forms that share similar biochemical and biophysical properties with amyloids associated with several human diseases. Here we report that fibrils polymerized in vitro from soluble forms sequester toxic species that can be released upon changing environmental conditions such as pH, ionic strength, and upon dilution. Our results indicate that basic pH (≥8.5), low NaCl concentrations (≤50 mm), and dilution (>10-fold) destabilize Mcc fibrils into more soluble species that are found to be toxic to the target cells. Additionally, we also found a similar conversion of non-toxic fibrils into highly toxic oligomers using Mcc aggregates produced in vivo. Moreover, the soluble protein released from fibrils is able to rapidly polymerize into amyloid fibrils under fibril-forming conditions and to efficiently seed aggregation of monomeric Mcc. Our findings indicate that fibrillar forms of Mcc constitute a reservoir of toxic oligomeric species that is released into the medium upon changing the environmental conditions. These findings may have substantial implications to understand the dynamic process of interconversion between toxic and non-toxic aggregated species implicated in protein misfolding diseases.
authors.affiliation: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Houston Medical School, Houston, Texas 77030, USA
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahnawaz
authors.forename: Claudio
authors.initials: C
authors.lastname: Soto
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology / Q000648:ultrastructure; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001430:Bacteriocins / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D002850:Chromatography, Gel; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D006863:Hydrogen-Ion Concentration; D050296:Microbial Viability; D009994:Osmolar Concentration; D010316:Particle Size; D055503:Protein Multimerization; D055550:Protein Stability; D012965:Sodium Chloride / Q000737:chemistry
chemical_list: D000682:Amyloid; D000900:Anti-Bacterial Agents; D001430:Bacteriocins; C020411:microcin; D012965:Sodium Chloride