title: Methionine oxidation enhances κ-casein amyloid fibril formation.
abstract: The effects of protein oxidation, for example of methionine residues, are linked to many diseases, including those of protein misfolding, such as Alzheimer's disease. Protein misfolding diseases are characterized by the accumulation of insoluble proteinaceous aggregates comprised mainly of amyloid fibrils. Amyloid-containing bodies known as corpora amylacea (CA) are also found in mammary secretory tissue, where their presence slows milk flow. The major milk protein κ-casein readily forms amyloid fibrils under physiological conditions. Milk exists in an extracellular oxidizing environment. Accordingly, the two methionine residues in κ-casein (Met(95) and Met(106)) were selectively oxidized and the effects on the fibril-forming propensity, cellular toxicity, chaperone ability, and structure of κ-casein were determined. Oxidation resulted in an increase in the rate of fibril formation and a greater level of cellular toxicity. β-Casein, which inhibits κ-casein fibril formation in vitro, was less effective at suppressing fibril formation of oxidized κ-casein. The ability of κ-casein to prevent the amorphous aggregation of target proteins was slightly enhanced upon methionine oxidation, which may arise from the protein's greater exposed surface hydrophobicity. No significant changes to κ-casein's intrinsically disordered structure occurred upon oxidation. The enhanced rate of fibril formation of oxidized κ-casein, coupled with the reduced chaperone ability of β-casein to prevent this aggregation, may affect casein-casein interaction within the casein micelle and thereby promote κ-casein aggregation and contribute to the formation of CA.
authors.affiliation: School of Chemistry & Physics, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Tomas
authors.initials: T
authors.lastname: Koudelka
authors.forename: Francis C
authors.initials: FC
authors.lastname: Dehle
authors.forename: Ian F
authors.initials: IF
authors.lastname: Musgrave
authors.forename: Peter
authors.initials: P
authors.lastname: Hoffmann
authors.forename: John A
authors.initials: JA
authors.lastname: Carver
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002364:Caseins / Q000737:chemistry* / Q000378:metabolism; D002417:Cattle; D008715:Methionine / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D016716:PC12 Cells; D051381:Rats
chemical_list: D000682:Amyloid; D002364:Caseins; D008715:Methionine