Methionine Oxidation Enhances
κ-Casein Amyloid
Fibril Formation
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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<sub>95</sub> and Met<sub>106</sub>) 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