Methionine oxidized apolipoprotein A‐I at the crossroads of HDL biogenesis and amyloid formation

What is it about?

Apolipoprotein A-I (apoA-I) is a protein that transport cholesterol and fats in our blood, thus promoting cardiovascular health. Dysfunction of apoA-I is a well-established factor in atherosclerosis development, the primary cause of cardiovascular disease. Oxidation of apoA-I leads to dysfunction and in the atherosclerotic lesions, apoA-I is heavily oxidized. In parallel, high levels of amyloids can be detected in atherosclerotic lesions. Amyloids are insoluble material that is produced when proteins get destabilized and lose their native structure. Notably, atherosclerosis-related amyloids are predominantly composed of apoA-I In the current study, we elucidated the structural mechanism whereby oxidation predisposes apoA-I to aggregation into amyloids. In particular, oxidation of a specific amino acid in apoA-I, methionine, dramatically decreased the thermodynamic stability of apoA-I and promoted aggregation into amyloids. Surprisingly, methionine oxidized apoA I was more efficient than intact apoA-I as recipient of cellular cholesterol, one important beneficial functions of this protein. In parallel we also found that macrophages, immune cells directly involved in the process of atherosclerosis development, associated with oxidized apoA-I, but did not associate with intact apoA-I, suggesting yet unexplored physiological consequences of oxidized apoA-I. Also of physiological importance, we discovered that not only the oxidized protein was prone to aggregate in amyloid material, but amyloids formed by oxidized apoA-I could also induce secondary amyloid aggregation in intact non-oxidized apoA-I. In conclusion, our studies identified oxidized apoA-I as an intermediate species at the crossroads of two physiologically important routes: beneficial interaction with cell-membranes to bind lipids or detrimental aggregation into non functional amyloids.

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