Novel Redox-Dependent Esterase Activity (EC 184.108.40.206) for DJ-1: Implications for Parkinson’s Disease
AbstractMutations the in human DJ-1 (hDJ-1) gene are associated with early-onset autosomal recessive forms of Parkinson’s disease (PD). hDJ-1/parkinsonism associated deglycase (PARK7) is a cytoprotective multi-functional protein that contains a conserved cysteine-protease domain. Given that cysteine-proteases can act on both amide and ester substrates, we surmised that hDJ-1 possessed cysteine-mediated esterase activity. To test this hypothesis, hDJ-1 was overexpressed, purified and tested for activity towards 4-nitrophenyl acetate (pNPA) as µmol of pNPA hydrolyzed/min/mg·protein (U/mg protein). hDJ-1 showed maximum reaction velocity esterase activity (Vmax = 235.10 ± 12.00 U/mg protein), with a sigmoidal fit (S0.5 = 0.55 ± 0.040 mM) and apparent positive cooperativity (Hill coefficient of 2.05 ± 0.28). A PD-associated mutant of DJ-1 (M26I) lacked activity. Unlike its protease activity which is inactivated by reactive oxygen species (ROS), esterase activity of hDJ-1 is enhanced upon exposure to low concentrations of hydrogen peroxide (<10 µM) and plateaus at elevated concentrations (>100 µM) suggesting that its activity is resistant to oxidative stress. Esterase activity of DJ-1 requires oxidation of catalytic cysteines, as chemically protecting cysteines blocked its activity whereas an oxido-mimetic mutant of DJ-1 (C106D) exhibited robust esterase activity. Molecular docking studies suggest that C106 and L126 within its catalytic site interact with esterase substrates. Overall, our data show that hDJ-1 contains intrinsic redox-sensitive esterase activity that is abolished in a PD-associated mutant form of the hDJ-1 protein. View Full-Text
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Vázquez-Mayorga, E.; Díaz-Sánchez, Á.G.; Dagda, R.K.; Domínguez-Solís, C.A.; Dagda, R.Y.; Coronado-Ramírez, C.K.; Martínez-Martínez, A. Novel Redox-Dependent Esterase Activity (EC 220.127.116.11) for DJ-1: Implications for Parkinson’s Disease. Int. J. Mol. Sci. 2016, 17, 1346.
Vázquez-Mayorga E, Díaz-Sánchez ÁG, Dagda RK, Domínguez-Solís CA, Dagda RY, Coronado-Ramírez CK, Martínez-Martínez A. Novel Redox-Dependent Esterase Activity (EC 18.104.22.168) for DJ-1: Implications for Parkinson’s Disease. International Journal of Molecular Sciences. 2016; 17(8):1346.Chicago/Turabian Style
Vázquez-Mayorga, Emmanuel; Díaz-Sánchez, Ángel G.; Dagda, Ruben K.; Domínguez-Solís, Carlos A.; Dagda, Raul Y.; Coronado-Ramírez, Cynthia K.; Martínez-Martínez, Alejandro. 2016. "Novel Redox-Dependent Esterase Activity (EC 22.214.171.124) for DJ-1: Implications for Parkinson’s Disease." Int. J. Mol. Sci. 17, no. 8: 1346.
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