Superoxide dismutase protects calcineurin from inactivation.
Calcineurin is the only protein phosphatase known to be under the control of Ca2+ and calmodulin. It is targeted by immunosuppressive drugs and has a critical role in T-cell activation. It is specifically inhibited by immunosuppressant immunophilin complexes, which enabled its function in regulating a wide range of cellular responses to Ca2+-mobilizing signals to be identified. Calcineurin in situ is 10-20 times more active than in the purified form and is subject to a time- and Ca2+/calmodulin-dependent reversible inactivation that is facilitated by small, heat-stable molecules. Here we identify a factor that prevents the inactivation of calcineurin in vitro and in vivo as the enzyme superoxide dismutase, which indicates that inactivation may be the result of oxidative damage to the Fe-Zn active centre of calcineurin. The redox state of iron provides a mechanism to regulate calcineurin activity by desensitizing the enzyme and coupling Ca2+-dependent protein dephosphorylation to the redox state of the cell. The protection of calcineurin against inactivation by superoxide dismutase constitutes a new physiological role for this enzyme which enables the Ca2+-dependent regulation of cellular processes to be modulated by the redox potential.
Wang
X
X
Laboratory of Biochemistry, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.
Culotta
V C
VC
Klee
C B
CB
D000818:Animals; D001921:Brain / Q000201:enzymology; D019703:Calcineurin; D002118:Calcium / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D010084:Oxidation-Reduction; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013482:Superoxide Dismutase / Q000378:metabolism*
D002148:Calmodulin-Binding Proteins; D013482:Superoxide Dismutase; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002118:Calcium