In vitro oxidative inactivation of human presequence protease (hPreP)

• The mitochondrial peptidasome called presequence protease (Prep) is responsible for the degradation of presequences and other unstructured peptides including the amyloid-beta, peptide, whose accumulation may have deleterious effects on mitochondrial function. Recent studies showed that PreP activity is reduced in Alzheimer disease (AD) patients and AD mouse models compared to controls, which correlated with an enhanced reactive oxygen species production in mitochondria. In this study, we have investigated the effects of a biologically relevant oxidant, hydrogen peroxide (H2O2), on the activity of recombinant human PreP (hPreP). H2O2 inhibited hPreP activity in a concentration-dependent manner, resulting in oxidation of amino acid residues (detected by carbonylation) and lowered protein stability. Substitution of the evolutionarily conserved methionine 206 for leucine resulted in increased sensitivity of hPreP to oxidation, indicating a possible protective role of M2O6 as internal antioxidant. The activity of hPreP oxidized at low concentrations of H2O2 could be restored by methionine sulfoxide reductase A (MsrA), an enzyme that localizes to the mitochondrial matrix, suggesting that hPreP constitutes a substrate for MsrA. In summary, our in vitro results suggest a possible redox control of hPreP in the mitochondrial matrix and support the protective role of the conserved methionine 206 residue as an internal antioxidant.

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Keyword

Mitochondria

Presequence protease

Peptide degradation

Oxidation

Methionine

Free radicals

Publication and Content Type

ref (subject category)

art (subject category)