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The Catalytic Subunit of Protein Phosphatase 2A is a Highly Sensitive Target of Protein Disulfide‐Mediated Oxidative Stress
Author(s) -
Foley Timothy D,
Stredny Coral M,
Coppa Teresa
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a618-a
Subject(s) - protein phosphatase 2 , oxidative stress , protein subunit , chemistry , thiol , glutathione , oxidative phosphorylation , biochemistry , enzyme , gene
Mounting evidence suggests that protein phosphatase 2A (PP2A), a key regulator of neuronal function, may be an important target of disulfide‐mediated oxidative stress and that thiol oxidation‐based inhibition of PP2A activity may be a cause of oxidative stress‐induced neurotoxicity. However, the nature of the physiologically‐relevant disulfides that PP2A may form and the relationship of disulfide formation to inhibition of PP2A activity in response to oxidative stress remain unclear. The present results demonstrate using a high molecular weight soluble fraction (HMWSF) from rat brain as a source of PP2A that the catalytic subunit (PP2A C ) of the enzyme readily formed intermolecular disulfides with other proteins from the brain and, perhaps, an intramolecular disulfide under the mild oxidative stress achieved in the absence of thiol reducing agent. Thiol oxidation‐based inhibition of PP2A activity, however, required the addition of hydrogen peroxide and was associated with more extensive disulfide cross‐linking and the incorporation of PP2A C into very high molecular weight protein complexes. Notably, other proteins from the HMWSF, including the synaptosomal‐associated protein of 25 kDa (SNAP‐25), but not PP2A C formed a mixed disulfide with biotinyl‐glutathione. These results demonstrate that the catalytic subunit of PP2A is a highly sensitive target of protein disulfide‐mediated oxidative stress and suggest that the functional consequences of disulfide formation may depend on the level of oxidative stress.