Oxidative inhibition of protein phosphatase 2A activity: role of catalytic subunit disulfides.
A molecular basis for the inhibition of brain protein phosphatase 2A (PP2A) activity by oxidative stress was examined in a high-speed supernatant (HSS) fraction from rat cerebral cortex. PP2A activity was subject to substantial disulfide reducing agent-reversible inhibition in the HSS fraction. Results of gel electrophoresis support the conclusions that inhibition of PP2A activity was associated with the both the disulfide cross-linking of the catalytic subunit (PP2A(C)) of the enzyme to other brain proteins and with the formation of an apparent novel intramolecular disulfide bond in PP2A(C). Additional findings that the vicinal dithiol cross-linking reagent phenylarsine oxide (PAO) produced a potent dithiothreitol-reversible inhibition of PP2A activity suggest that the cross-linking of PP2A(C) vicinal thiols to form an intramolecular disulfide bond may be sufficient to inhibit PP2A activity under oxidative stress. We propose that the dithiol-disulfide equilibrium of a vicinal thiol pair of PP2A(C) may confer redox sensitivity on cellular PP2A.
Foley
Timothy D
TD
Department of Chemistry, University of Scranton, 800 Linden St., Scranton, PA 18510, USA. foleyt2@scranton.edu
Petro
Laura A
LA
Stredny
Coral M
CM
Coppa
Teresa M
TM
D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D002540:Cerebral Cortex / Q000201:enzymology; D003432:Cross-Linking Reagents; D004220:Disulfides / Q000378:metabolism*; D010084:Oxidation-Reduction; D010720:Phosphines / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D021122:Protein Subunits; D051381:Rats; D019163:Reducing Agents / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism
D001152:Arsenicals; D003432:Cross-Linking Reagents; D004220:Disulfides; D010720:Phosphines; D010744:Phosphoric Monoester Hydrolases; D054648:Protein Phosphatase 2; D021122:Protein Subunits; D019163:Reducing Agents; D013438:Sulfhydryl Compounds; C029341:oxophenylarsine; C080938:tris(2-carboxyethyl)phosphine; C045903:phosphothreonine phosphatase